Biochemistry, Genetics and Molecular Biology › Molecular Biology

Hedgehog Signaling Pathway Studies

Works Count: 29429

Wikipedia

Description

This cluster of papers focuses on the role of Hedgehog signaling in both animal development and cancer, particularly its involvement in tumorigenesis, stem cell renewal, and the progression of specific cancers such as pancreatic cancer and basal cell carcinoma. The papers also discuss the mechanisms of Hedgehog pathway inhibition and its potential as a therapeutic target for cancer treatment.

Keywords

Hedgehog Signaling; Cancer; Development; Pathway Inhibition; Tumorigenesis; Stem Cells; Pancreatic Cancer; Gli Proteins; Smoothened; Basal Cell Carcinoma

The Hedgehog and Wnt signalling pathways in cancer

2001-05-01

Jussi Taipale , Philip A. Beachy

Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb

1998-01-01

Jin Jiang , Gary Struhl

Activating Smoothened mutations in sporadic basal-cell carcinoma

1998-01-01

Jingwu Xie , Maximilien Murone , Shiuh-Ming Luoh +7 more

HedgehogandBmpGenes Are Coexpressed at Many Diverse Sites of Cell–Cell Interaction in the Mouse Embryo

1995-11-01

Mark Joseph Bitgood , Andrew P. McMahon

TGF-β-induced epithelial to mesenchymal transition

2009-01-20

Jian Xu , Samy Lamouille , Rik Derynck

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Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma

2009-09-03

Daniel D. Von Hoff , Patricia LoRusso , Charles M. Rudin +7 more

Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety … Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug.

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Mutations in the human Sonic Hedgehog gene cause holoprosencephaly

1996-11-01

Erich Roessler , Elena Belloni , Karin Gaudenz +5 more

Multiple Nevoid Basal-Cell Epithelioma, Jaw Cysts and Bifid Rib

1960-05-05

Robert J. Gorlin , Robert W. Goltz

IN 1951 Binkley and Johnson1 reported the case of a thirty-one-year-old woman with basal-cell nevi, agenesis of the corpus callosum and dental cysts. The skin lesions, appearing in childhood, extended … IN 1951 Binkley and Johnson1 reported the case of a thirty-one-year-old woman with basal-cell nevi, agenesis of the corpus callosum and dental cysts. The skin lesions, appearing in childhood, extended to involve the neck, face, thorax, abdomen, upper arms and back. The jaw lesions, noted when she was about sixteen years of age, were diagnosed as dentigerous cysts. She was given roentgenotherapy to the jaw for seven years. Subsequently, fibrosarcoma developed in this area and metastasized to the lungs and vertebras, resulting in death. A fibroma of the ovary was surgically removed, and bifid sixth rib and absence of the . . .

Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways

2005-11-14

Lionel Larue , Alfonso Bellacosa

Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development

1996-10-11

Jeffery A. Porter , Keith E. Young , Philip A. Beachy

Hedgehog (Hh) proteins comprise a family of secreted signaling molecules essential for patterning a variety of structures in animal embryogenesis. During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its … Hedgehog (Hh) proteins comprise a family of secreted signaling molecules essential for patterning a variety of structures in animal embryogenesis. During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. This use of cholesterol to modify embryonic signaling proteins may account for some of the effects of perturbed cholesterol biosynthesis on animal development.

Altered Neural Cell Fates and Medulloblastoma in Mouse patched Mutants

1997-08-22

Lisa V. Goodrich , Ljiljana Milenković , Kay M. Higgins +1 more

The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS). Functions of PTC were investigated by … The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS). Functions of PTC were investigated by inactivating the mouse gene. Mice homozygous for the ptc mutation died during embryogenesis and were found to have open and overgrown neural tubes. Two Shh target genes, ptc itself and Gli, were derepressed in the ectoderm and mesoderm but not in the endoderm. Shh targets that are, under normal conditions, transcribed ventrally were aberrantly expressed in dorsal and lateral neural tube cells. Thus Ptc appears to be essential for repression of genes that are locally activated by Shh. Mice heterozygous for the ptc mutation were larger than normal, and a subset of them developed hindlimb defects or cerebellar medulloblastomas, abnormalities also seen in BCNS patients.

Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity

1993-12-01

Yann Echelard , Douglas J. Epstein , Benoit St‐Jacques +4 more

The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog

1996-11-01

Donna M. Stone , Mary Hynes , Mark Armanini +7 more

Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein

1996-08-02

Andrea Vortkamp , Kaechoong Lee , Beate Lanske +3 more

Proper regulation of chondrocyte differentiation is necessary for the morphogenesis of skeletal elements, yet little is known about the molecular regulation of this process. A chicken homolog of Indian hedgehog … Proper regulation of chondrocyte differentiation is necessary for the morphogenesis of skeletal elements, yet little is known about the molecular regulation of this process. A chicken homolog of Indian hedgehog (Ihh), a member of the conserved Hedgehog family of secreted proteins that is expressed during bone formation, has now been isolated. Ihh has biological properties similar to those of Sonic hedgehog (Shh), including the ability to regulate the conserved targets Patched (Ptc) and Gli. Ihh is expressed in the prehypertrophic chondrocytes of cartilage elements, where it regulates the rate of hypertrophic differentiation. Misexpression of Ihh prevents proliferating chondrocytes from initiating the hypertrophic differentiation process. The direct target of Ihh signaling is the perichondrium, where Gli and Ptc flank the expression domain of Ihh. Ihh induces the expression of a second signal, parathyroid hormone-related protein (PTHrP), in the periarticular perichondrium. Analysis of PTHrP (−/−) mutant mice indicated that the PTHrP protein signals to its receptor in the prehypertrophic chondrocytes, thereby blocking hypertrophic differentiation. In vitro application of Hedgehog or PTHrP protein to normal or PTHrP (−/−) limb explants demonstrated that PTHrP mediates the effects of Ihh through the formation of a negative feedback loop that modulates the rate of chondrocyte differentiation.

Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma

2014-05-22

Andrew D. Rhim , Paul E. Oberstein , Dafydd Thomas +7 more

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Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis

2003-09-14

Sarah P. Thayer , Marina Pasca di Magliano , Patrick W. Heiser +7 more

Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1

2011-07-29

Nishant Agrawal , Mitchell J. Frederick , Curtis R. Pickering +7 more

The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies. The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies.

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Vertebrate Smoothened functions at the primary cilium

2005-08-31

Kevin C. Corbit , Pia Aanstad , Veena Singla +3 more

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

2015-04-07

Naoko Takebe , Lucio Miele , Pamela Jo Harris +5 more

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Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm

1995-09-01

Karel F. Liem , Gabi Tremml , Henk Roelink +1 more

The cellular interactions that control the differentiation of dorsal cell types from neural progenitors have been examined in neural plate explants. Certain genes that are expressed in the dorsal neural … The cellular interactions that control the differentiation of dorsal cell types from neural progenitors have been examined in neural plate explants. Certain genes that are expressed in the dorsal neural tube are initially expressed uniformly within the neural plate and appear to achieve their dorsal restriction through a Sonic hedgehog (SHH)-mediated repressive signal from the notochord. The acquisition of definitive dorsal cell fates, however, requires a contact-dependent signal from the epidermal ectoderm. BMP4 and BMP7 are expressed in the epidermal ectoderm, and both proteins mimic its inductive activity. BMP4 and a related gene, DSL1, are subsequently expressed by cells in the dorsal neural tube. The differentiation of dorsal cell types, therefore, appears to be initiated at the neural plate stage and to involve the opponent activities of a BMP-mediated dorsalizing signal from the epidermal ectoderm and a SHH-mediated ventralizing signal from the notochord.

Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells

2005-06-01

Johan H. van Es , Mariëlle van Gijn , Orbicia Riccio +7 more

Human Homolog of patched , a Candidate Gene for the Basal Cell Nevus Syndrome

1996-06-14

Ronald L. Johnson , Alana Rothman , Jingwu Xie +7 more

The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations … The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a transmembrane protein that in Drosophila acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues. The human PTC gene appears to be crucial for proper embryonic development and for tumor suppression.

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer

2003-03-01

D. Neil Watkins , David M. Berman , Scott G. Burkholder +3 more

Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function

1996-10-01

Chin Chiang , Ying Litingtung , Eric Lee +4 more

Tumour stem cells and drug resistance

2005-04-01

Michael Dean , Tito Fojo , Susan E. Bates

Patched1 Regulates Hedgehog Signaling at the Primary Cilium

2007-07-19

Rajat Rohatgi , Ljiljana Milenković , Matthew P. Scott

Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog … Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.

Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells

2006-12-01

Sara Piccirillo , Brent A. Reynolds , Nadia Zanetti +7 more

PTH/PTHrP Receptor in Early Development and Indian Hedgehog—Regulated Bone Growth

1996-08-02

Beate Lanske , Andrew C. Karaplis , Kaechong Lee +7 more

The PTH/PTHrP receptor binds to two ligands with distinct functions: the calcium-regulating hormone, parathyroid hormone (PTH), and the paracrine factor, PTH-related protein (PTHrP). Each ligand, in turn, is likely to … The PTH/PTHrP receptor binds to two ligands with distinct functions: the calcium-regulating hormone, parathyroid hormone (PTH), and the paracrine factor, PTH-related protein (PTHrP). Each ligand, in turn, is likely to activate more than one receptor. The functions of the PTH/PTHrP receptor were investigated by deletion of the murine gene by homologous recombination. Most PTH/PTHrP receptor (−/−) mutant mice died in mid-gestation, a phenotype not observed in PTHrP (−/−) mice, perhaps because of the effects of maternal PTHrP. Mice that survived exhibited accelerated differentiation of chondrocytes in bone, and their bones, grown in explant culture, were resistant to the effects of PTHrP and Sonic hedgehog. These results suggest that the PTH/PTHrP receptor mediates the effects of Indian Hedgehog and PTHrP on chondrocyte differentiation.

Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours

2003-09-14

David M. Berman , Sunil Karhadkar , Anirban Maitra +7 more

The mechanisms of Hedgehog signalling and its roles in development and disease

2013-05-30

James Briscoe , Pascal P. Thérond

Small molecule modulation of Smoothened activity

2002-10-21

James Chen , Jussi Taipale , Keith E. Young +2 more

Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms … Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.

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The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis

1996-11-20

Charis Eng

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); … Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making.Correlative survey study of 477 MEN 2 families.Eighteen tertiary referral centers worldwide.A total of 477 independent MEN 2 families.Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family.There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors.This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Hedgehog Signaling in Development and Cancer

2008-12-01

Jin Jiang , Chi-chung Hui

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Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma

2012-06-07

Aleksandar Sekulić , Michael R. Migden , Anthony E. Oro +7 more

Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. … Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.

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Hedgehog: functions and mechanisms

2008-09-15

Markku Varjosalo , Jussi Taipale

The Hedgehog (Hh) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan. The use of a single morphogen for such … The Hedgehog (Hh) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan. The use of a single morphogen for such a wide variety of functions is possible because cellular responses to Hh depend on the type of responding cell, the dose of Hh received, and the time cells are exposed to Hh. The Hh gradient is shaped by several proteins that are specifically required for Hh processing, secretion, and transport through tissues. The mechanism of cellular response, in turn, incorporates multiple feedback loops that fine-tune the level of signal sensed by the responding cells. Germline mutations that subtly affect Hh pathway activity are associated with developmental disorders, whereas somatic mutations activating the pathway have been linked to multiple forms of human cancer. This review focuses broadly on our current understanding of Hh signaling, from mechanisms of action to cellular and developmental functions. In addition, we review the role of Hh in the pathogenesis of human disease and the possibilities for therapeutic intervention.

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Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

2009-05-22

Kenneth P. Olive , Michael A. Jacobetz , Christian J. Davidson +7 more

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory … Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

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Hedgehog signaling in animal development: paradigms and principles

2001-12-01

Philip W. Ingham , Andrew P. McMahon

Since their isolation in the early 1990s, members of the Hedgehog family of intercellular signaling proteins have come to be recognized as key mediators of many fundamental processes in embryonic … Since their isolation in the early 1990s, members of the Hedgehog family of intercellular signaling proteins have come to be recognized as key mediators of many fundamental processes in embryonic development. Their activities are central to the growth, patterning, and morphogenesis of many different regions within the body plans of vertebrates and insects, and most likely other invertebrates. In some contexts, Hedgehog signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens regulating cell proliferation or as inducing factors controlling the form of a developing organ. These diverse functions of Hedgehog proteins raise many intriguing questions about their mode of operation. How do these proteins move between or across fields of cells? How are their activities modulated and transduced? What are their intracellular targets? In this article we review some well-established paradigms of Hedgehog function inDrosophila and vertebrate development and survey the current understanding of the synthesis, modification, and transduction of Hedgehog proteins. Embryological studies over much of the last century that relied primarily on the physical manipulation of cells within the developing embryo or fragments of the embryo in culture, provided many compelling examples for the primacy of cell–cell interactions in regulating invertebrate and vertebrate development. The subsequent identification of many of the signaling factors that mediate cellular communication has led to two general conclusions. First, although there are many important signals, most of these fall into a few large families of secreted peptide factors: theWnt (Wodarz and Nusse 1998), fibroblast growth factor (Szebenyi and Fallon 1999), TGFsuperfamily (Massague and Chen 2000), plateletderived growth factor (Betsholtz et al. 2001), ephrin (Bruckner and Klein 1998), and Hedgehog families. Second, parallel studies in invertebrate and vertebrate systems have shown that although the final outcome might look quite different (e.g., a fly vs. a mouse), there is a striking conservation in the deployment of members of the same signaling families to regulate development of these seemingly quite different organisms. This review focuses on one of the most intriguing examples of this phenomenon, that of the Hedgehog family. As with many of the advances in our understanding of the genetic regulation of animal development, hedgehog (hh) genes owe their discovery to the pioneering work of Nusslein-Volhard and Wieschaus (1980). In their screen for mutations that disrupt the Drosophila larval body plan, these authors identified several that cause the duplication of denticles (spiky cuticular processes that decorate the anterior half of each body segment) and an accompanying loss of naked cuticle, characteristic of the posterior half of each segment (see Fig. 1). The ensuing appearance of a continuous lawn of denticles projecting from the larval cuticle evidently suggested the spines of a hedgehog to the discoverers, hence the origin of the name of one of these genes. Other loci identified by mutants with this phenotype included armadillo, gooseberry, and wingless (wg). In contrast, animals mutant for the aptly named naked gene showed the converse phenotype, with denticle belts replaced by naked cuticle in every segment. On the basis of these mutant phenotypes, Nusslein-Volhard and Wieschaus (1980) proposed that these so-called segment-polarity genes regulate pattern within each of the segments of the larval body, individual genes acting within distinct subregions of the emerging segmental pattern. The first important breakthrough in unraveling how segment-polarity genes act came in the mid-1980s with the cloning of two members of the class, wingless and engrailed (en). Wg was shown to be the ortholog of the vertebrate proto-oncogene int1 (subsequently renamed Wnt1 and the founder member of the Wnt family of secreted peptide factors; Rijsewijk et al. 1987), whereas the sequence of en revealed that it encodes a homeodomaincontaining transcription factor (Fjose et al. 1985; Poole et al. 1985). Intriguingly, the two genes were found to be expressed in adjacent narrow stripes of cells in each segment (Martinez Arias et al. 1988). A close spatial relationship between Wnt1 and En expression domains was also reported in the primordial midbrain and hindbrain of the vertebrate embryo (McMahon et al. 1992). AnalyWe dedicate this review to the memory of our dear friend and colleague Rosa Beddington, whose encouragement led to our initial collaboration. 3Corresponding authors. E-MAIL [email protected]; FAX 0114-222-288. E-MAIL [email protected]; FAX (617) 496-3763. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ gad.938601.

Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation

1999-08-15

Benoit St‐Jacques , Matthias Hammerschmidt , Andrew P. McMahon

Benoit St-Jacques, Matthias Hammerschmidt, and Andrew P. McMahon Harvard University, Department of Molecular and Cellular Biology, Cambridge, Massachusetts 02138 USA Benoit St-Jacques, Matthias Hammerschmidt, and Andrew P. McMahon Harvard University, Department of Molecular and Cellular Biology, Cambridge, Massachusetts 02138 USA

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Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

2012-02-22

Marcel Kool , Andrey Korshunov , Marc Remke +7 more

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of … Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.

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Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449

2009-09-03

Charles M. Rudin , Christine L. Hann , John Laterra +7 more

Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old … Medulloblastoma is the most common malignant brain tumor in children. Aberrant activation of the hedgehog signaling pathway is strongly implicated in the development of some cases of medulloblastoma. A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms. Molecular analyses of tumor specimens obtained before treatment suggested that there was activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched homologue 1 (PTCH1), a key negative regulator of hedgehog signaling.

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Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome

1996-06-01

Heidi Hahn , Carol Wicking , Peter G. Zaphiropoulos +7 more

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of … The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

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Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened

2002-11-01

James Chen , Jussi Taipale , Michael K. Cooper +1 more

The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent … The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo). Cyclopamine also can reverse the retention of partially misfolded Smo in the endoplasmic reticulum, presumably through binding-mediated effects on protein conformation. These observations reveal the mechanism of cyclopamine's teratogenic and antitumor activities and further suggest a role for small molecules in the physiological regulation of Smo.

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HEDGEHOG-GLI1 Signaling Regulates Human Glioma Growth, Cancer Stem Cell Self-Renewal, and Tumorigenicity

2006-12-29

Virginie Clément , Pilar Sánchez‐Gómez , Nicolas de Tribolet +2 more

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Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog

1999-01-01

Robert J. Wechsler‐Reya , Matthew P. Scott

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Tissue repair and stem cell renewal in carcinogenesis

2004-11-01

Philip A. Beachy , Sunil Karhadkar , David M. Berman

Hedgehog-Regulated Processing of Gli3 Produces an Anterior/Posterior Repressor Gradient in the Developing Vertebrate Limb

2000-02-01

Baolin Wang , John F. Fallon , Philip A. Beachy

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Hedgehog Signaling and Bmi-1 Regulate Self-renewal of Normal and Malignant Human Mammary Stem Cells

2006-06-15

Suling Liu , Gabriela Dontu , Ilia D. Mantle +5 more

Abstract The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny … Abstract The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast “cancer stem cells” characterized as CD44+CD24−/lowLin−. These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells. (Cancer Res 2006; 66(12): 6063-71)

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Hepatogastroenterology

2011-10-18

Yidong Cai , Haoxuan Zheng , Wei Gong +2 more

In this study, we explored the role of the Hedgehog signaling pathway in liver regeneration.Retrorsine, partial hepatectomy and combined were utilized in mature Fisher344 rats. Specific assays, such as RT-PCR, … In this study, we explored the role of the Hedgehog signaling pathway in liver regeneration.Retrorsine, partial hepatectomy and combined were utilized in mature Fisher344 rats. Specific assays, such as RT-PCR, real-time PCR and immunohistochemistry were used to detect the constituents of the Hedgehog signaling pathway during liver regeneration.mRNA expression of Ihh, Ptc, Smo, Gli1, Gli2 and Gli3 were all shown in liver tissue homogenates in control/normal, retrorsine, partial hepatectomy and retrorsine/partial hepatectomy groups while no Shh expression was found. Real-time PCR analysis indicated that there were significant differences in Hedgehog signaling pathway-related constituents (Ihh, Ptc, Gli1 and Gli3) among the different treatment groups and at distinct time points in the same treatment group during liver regeneration. The data also suggested an interaction effect between different treatment and time to the variation of Ihh, Ptc, Gli1 and Gli3. The protein expression of Ptc and Gli1 in liver regeneration was confirmed by immunohistochemistry, which differed in the duration among different groups. Nevertheless, the protein expression of Ptc and Gli1 were not detected successfully by western blot.It appears that the Hedgehog signaling pathway may be involved in liver regeneration.

Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

2000-08-01

Jussi Taipale , James Chen , Michael K. Cooper +5 more

A stereotaxic atlas of the diencephalon of the cat

1960-01-01

Herbert H. Jasper , C. Ajmone-Marsan

FOXP2 mediates ZSCAN18 transcriptional activation to inhibit oral squamous cell carcinoma progression by blocking Hedgehog signaling

2025-06-24

Ling Niu , Guangyao Hu | Mammalian Genome

A posterior fossa mass in a 4‐year‐old female

2025-06-24

Victoria Huynh , M. Adelita Vizcaíno , Jonathan Schwartz +7 more | Brain Pathology

Real-world experience with first- versus second-line cemiplimab for advanced basal cell carcinoma.

2025-06-24

Viola K. DeTemple , Martin Kaatz , Eggert Stockfleth +7 more | European Journal of Cancer

Clinical Features and Management of Odontogenic Keratocysts in Gorlin Goltz Syndrome

2025-06-24

Jiang Li , Cheng Wan , Yuk Yee Leung +1 more | International Journal of Oral and Maxillofacial Surgery

Are OPG radiographs adequate surveillance for Gorlin Goltz syndrome patients?

2025-06-24

Emily Hill , U. Selbong | International Journal of Oral and Maxillofacial Surgery

Immunohistochemical expression of smoothened in periocular basal cell, squamous cell and sebaceous carcinomas

2025-06-20

Gustav Stålhammar , Baktiar Hasan , Krzysztof Kotowski +3 more | Scientific Reports

Abstract Inhibition of Smoothened (SMO), a key protein in the Hedgehog signaling pathway, is effective for locally advanced basal cell carcinoma (BCC), but is not yet used for sebaceous carcinoma … Abstract Inhibition of Smoothened (SMO), a key protein in the Hedgehog signaling pathway, is effective for locally advanced basal cell carcinoma (BCC), but is not yet used for sebaceous carcinoma (SEB) or squamous cell carcinoma (SCC). This study quantified SMO expression and its relationship to proliferative activity in non-nodular periocular BCC, SEB and SCC. Tumor samples from 47 patients (17 BCC, 15 SCC, and 15 SEB) were immunostained and analyzed digitally to assess SMO optical density and Ki67 hot-spot index. SMO expression was significantly higher in all tumor types than in surrounding stroma, with no inter-tumor differences. SMO correlated with mitotic count in BCC but not in SCC or SEB, whereas higher SMO consistently paralleled a higher Ki67 index across all three carcinomas. These findings indicate that SMO expression and proliferative activity are closely linked and suggest that Hedgehog inhibitors, proven in BCC, warrant clinical evaluation as adjuvant or neoadjuvant therapy for periocular SEB and SCC.

The Prognostic Value of the Hedgehog Signaling Pathway in Ovarian Cancer

2025-06-19

Noor Salman , Lars Hanker , Balázs Győrffy +3 more | International Journal of Molecular Sciences

The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway's genes play a role in … The hedgehog pathway is a major regulator of cell growth and differentiation during embryogenesis and early development. The literature suggests that variations in this pathway's genes play a role in tumor progression and response to therapy. This study aimed to assess the correlation between the expression levels of selected genes of this pathway and the progression-free and overall survival of ovarian cancer patients. Using the database Kaplan-Meier plotter, which includes the gene expression and survival data of 1565 ovarian cancer patients, higher expression levels of the genes SHH, PTCH1, PTCH2, and GLI1 displayed better survival correlations, while GLI, GLI3, and SUFU correlated with adverse outcomes. Further dissection revealed a differential impact of the genes in specific clinical-histopathological categories. Notably, higher expression levels of SUFU were associated with a negative impact on ovarian cancer patients under many clinical-histopathological aspects. These results shed new light on the role of these genes in the chemoresponsiveness of ovarian cancer, especially SUFU, which could be considered a novel indicator for poor prognosis in epithelial ovarian cancer.

A Case of Accidental Veratrum californicum (California False Hellebore) Toxicity

2025-06-19

Caitlin Roake , Charizza Grace Besmanos , Patil Armenian | Wilderness and Environmental Medicine

Gastroprotective activity of Jervine alkaloid from Veratrum album on gastric ulcer in rat

2025-06-18

Serdar Yiğit , Tuba Aydın , Nilnur Eyerci +6 more | Heliyon

Multifactorial Drug - A Revolution in the Treatment of Cancer by Inhibiting Hedgehog Pathway

2025-06-18

M. Santosh Kumar , Poornima D. Vijendra , Pratap G. Kenchappa +1 more | BENTHAM SCIENCE PUBLISHERS eBooks

In the human body, Hedgehog (Hh) signaling is an essential pathway and plays a major role in embryo development, tumorigenesis, distant metastasis, poor prognosis, and tissue patterning. The Hh pathway … In the human body, Hedgehog (Hh) signaling is an essential pathway and plays a major role in embryo development, tumorigenesis, distant metastasis, poor prognosis, and tissue patterning. The Hh pathway has three ligands in mammals: Sonic Hedgehog (SHh), Desert Hedgehog (DHh), and Indian Hedgehog (IHh). Malfunctions of this pathway are associated with diseases that include cancer. Cancer is one of the leading causes of death worldwide and factors like dietary habits, family history, obesity, environmental conditions, tobacco, and genetic factors affect the likelihood of developing cancer. The Hh signaling pathway through sporadic mutations is explicitly associated with cancer development and progression in various solid malignancies. Abnormal expression of the Hh signaling cascade has been reported in the development of basal cell carcinoma, breast, liver, prostate, colon, pancreas, and stomach cancer. Most researchers target the inhibition of the Hh signaling pathway and therefore it has emerged as a popular and validated therapeutic for the treatment of a wide range of cancers. A novel class of drugs such as sonidegib and vismodegib inhibits the Hedgehog pathway. There has been significant progress regarding the development of multifactorial drugs blocking Hh signaling. The discovery of multifactorial drugs to block the pathway has led to a new treatment that may significantly improve clinical outcomes in cancer patients. Several of these molecules have been included in the clinical testing stage. Yet finding a sustainable multifactorial inhibitor is still a challenge. This book chapter describes the Hh signaling pathway as a vital and multifactorial therapeutic target for cancer.

Molecular Studies

2025-06-17

Gregory A. Hosler , Mai P. Hoang | Cambridge University Press eBooks

Ficha de Eukoenenia virgemdalapa

2025-06-17

Maysa Fernanda Villela Rezende Souza , Marconi Souza‐Silva , Diego de Medeiros Bento +3 more | Datasets - Sistema SALVE - ICMBio

Hedgehog

2025-06-17

| Yale University Press eBooks

Prevalence of genetic alterations in basal cell carcinoma patients resistant to Hedgehog pathway inhibitors: a systematic review

2025-06-16

Suvijak Untaaveesup , Pornteera Srichana , Gynna Techataweewan +5 more | Annals of Medicine

Basal cell carcinoma (BCC) is a prevalent form of skin cancer that can be localized or metastatic. Current evidence supports the use of Hedgehog (Hh) pathway inhibitors for locally advanced … Basal cell carcinoma (BCC) is a prevalent form of skin cancer that can be localized or metastatic. Current evidence supports the use of Hedgehog (Hh) pathway inhibitors for locally advanced or metastatic BCC with resistance due to genetic alterations in the Hh pathway. This systematic review evaluated the prevalence of genetic alterations in Hh pathway genes in BCC. We conducted a comprehensive search across four databases: PubMed, EMBASE, SCOPUS and the Cochrane Library. We included articles reporting genetic alterations in patients with locally advanced or metastatic BCC resistant to Hh pathway inhibitors. We included three prospective cohort studies encompassing 27 samples, all of which were resistant to vismodegib treatment. The most prevalent genetic mutations in the Hh pathway were in PTCH1, SMO and TP53, with a pooled prevalence of 44.44%. This systematic review highlights the prevalence of genetic alterations in the Hh pathway in BCC and offers insights into the mechanisms involved in treatment resistance. Understanding the high resistance rates of these genes may facilitate the development of more effective targeted therapies for BCC.

Desert Hedgehog mediates stem Leydig cell differentiation through Ptch2/Gli1/Sf1 signaling axis

2025-06-15

Changle Zhao , Y CHEN , Lei Liu +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Desert Hedgehog (Dhh) mutations cause male infertility, testicular dysgenesis and Leydig cell dysfunction. However, the mechanisms by which Dhh regulates Leydig lineage commitment through receptor selectivity, transcriptional effector specificity, and … Desert Hedgehog (Dhh) mutations cause male infertility, testicular dysgenesis and Leydig cell dysfunction. However, the mechanisms by which Dhh regulates Leydig lineage commitment through receptor selectivity, transcriptional effector specificity, and steroidogenic coupling remain elusive. In this study, we identified a Dhh-Ptch2-Gli1-Sf1 signaling axis that is essential for the differentiation of stem Leydig cells (SLCs) by using CRISPR/Cas9-generated dhh/ptch2 mutants of Nile tilapia (Oreochromis niloticus) and SLC transplantation. The loss of Dhh recapitulated mammalian phenotypes, characterized by testicular hypoplasia and androgen insufficiency. Rescue experiments with 11-ketotesterone and a Dhh agonist, in conjunction with SLC transplantation, demonstrated that Dhh regulates the differentiation of SLCs rather than their survival. In vitro knockout experiments of ptch1 and ptch2 in SLCs indicated that Patched2 (Ptch2), rather than Ptch1, serves as the receptor for Dhh in SLCs. Furthermore, in vivo genetic rescue experiments indicated that while the ptch2 mutation did not affect testicular development, the Ptch2 mutation fully rescued the developmental disorders of the testes caused by the dhh mutation, thereby further corroborating Ptch2 as the receptor for Dhh in SLCs. Additionally, the Glioma-associated oncogene homolog 1 (Gli1, but not Gli2 or Gli3) functions as the transcriptional effector that drives the expression of steroidogenic factor 1 (sf1). Transcriptomic and functional analyses further established that Dhh signaling directly couples Sf1 to SLC differentiation. This study provides mechanistic insights into Dhh-related Leydig cell dysfunction and presents novel targets for regenerative therapies.

Downregulation of S6 Kinase and Hedgehog–Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation

2025-06-14

Maxim Kebenko , Ruimeng Zhuang , Konstantin Hoffer +7 more | International Journal of Molecular Sciences

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem … Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog-Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog-Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells.

PKR Inhibition Reduces High Glucose and H2O2-Induced Injury in Rat Renal Epithelial Cells by Suppressing the Sonic Hedgehog Pathway

2025-06-12

Ganesh Panditrao Lahane , Dishank Aorandekar , Audesh Bhat +1 more | Experimental Cell Research

Bioanalytical Method Development and Validation for Quantification of an Anti-Neoplastic Agent - Glasdegib by using LC–MS/MS (ESI) in Human Plasma

2025-06-12

Yamarthi Venkateswara Rao , Jithendra Chimakurthy , Srinivasa Babu Puttagunta | Current Trends in Biotechnology and Pharmacy

A Characterization of Axolotl Digit Regeneration: Conserved Mechanisms, Divergent Patterning, and a Critical Role for Hedgehog Signaling

2025-06-06

Jackson R. Griffiths , Melissa Miller , Timothy J. Duerr +2 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Axolotl digits offer an experimentally versatile model for studying complex tissue regeneration. Here, we provide a comprehensive morphological and molecular characterization of digit regeneration, revealing both conserved features and … Abstract Axolotl digits offer an experimentally versatile model for studying complex tissue regeneration. Here, we provide a comprehensive morphological and molecular characterization of digit regeneration, revealing both conserved features and notable divergences from classical limb regeneration. Digit blastemas progress through similar morphological stages, are nerve-dependent, contain key regenerative cell populations, and express many canonical morphogens and mitogens. However, they exhibit minimal expression of the A-P patterning genes Shh, Fgf8, and Grem1 ; suggesting distal outgrowth and patterning occur independently of these signals. Joint regenerative fidelity varies significantly across digits and cannot be explained by differences in nerve supply, cell proliferation, or differential expression of any patterning genes assessed in this study. Furthermore, functional experiments reveal Hedgehog signaling is essential for interphalangeal joint regeneration, but activation alone is insufficient to improve fidelity in less robust digits. This system combines experimental accessibility with intrinsic variation in regenerative outcomes, making it an ideal platform to identify critical determinants of successful tissue regeneration and refine models of appendage patterning.

Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival

2025-06-03

Julie Talbot , Joanna Fombonne , Jacob Torrejón +7 more | Nature Communications

Netrin-1 signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, … Netrin-1 signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, a monoclonal netrin-1 blocking antibody (anti-netrin-1 mAb/NP137) has been preclinically developed and netrin-1 blockade has recently been investigated in phase 1 and 2 clinical trials in several adult cancers. Here, we investigate the role of netrin-1 in the most common malignant pediatric brain cancer, Medulloblastoma. Interestingly, we find that netrin-1 is upregulated in medulloblastoma subgroups associated with developmental dysregulation, in particular in medulloblastoma with Sonic Hedgehog (SHH) activation. First, we demonstrate that genetic deletion of netrin-1 or systemic treatment with the clinical-stage anti-netrin-1 blocking antibody significantly reduces tumor growth in vivo in various orthotopic models of SHH medulloblastomas. Second, in vitro and in vivo, we unexpectedly uncover that SHH medulloblastomas treated with an SHH-inhibitor targeting Smoothened (SMO) increase netrin-1 expression, paving the way for combinatorial therapy. In line with that, we next show that netrin-1 blockade potentiates the efficacy of SMO inhibitor therapy in vivo. Together, our data indicate that, netrin-1 blockade, used as monotherapy or in combination with SMO inhibitors, is a promising therapeutic strategy in SHH medulloblastomas.

Clinical features and management of odontogenic keratocysts in Gorlin–Goltz syndrome

2025-06-01

Joyce Tin Wing Li , Changhua Wan , Andy Wai Kan Yeung +2 more | International Journal of Oral and Maxillofacial Surgery

Retraction: “Possible involvement of the Hedgehog and PDPK1-Akt pathways in the growth and migration of small-cell lung cancer”

2025-06-01

| Journal of International Medical Research

IKZF3 Promotes Gastric Cancer Progression via Hedgehog Signaling Activation and Is Targetable by SANT-1

2025-06-01

Muhammad Ali , Shantanu Baral , Jun Ren +4 more | Acta Biochimica et Biophysica Sinica

Cranial Nerve XII Palsy Mimicking Tongue Angioedema

2025-06-01

S. Sridhara | The Journal of Allergy and Clinical Immunology In Practice

Steroidal alkaloids from the rhizomes of Veratrum stenophyllum with anti-inflammatory potential

2025-06-01

Xiaoting Wang , B.K.H. Tan , X. H. Wu +5 more | Fitoterapia

Balancing SHH and BMP/FGF10 to specify tuberal hypothalamic neurons and glia

2025-06-01

Kavitha Chinnaiya , Ian Groves , Elizabeth Manning +5 more | Developmental Biology

Garcinone C suppressed the proliferation of gastric cancer cells through regulating Hedgehog signaling

2025-05-30

Y Zhou , Jin Tae Kim , Jung Won Kwon +5 more | bioRxiv (Cold Spring Harbor Laboratory)

Garcinone C, a xanthone derived from Garcinia mangostana L, possesses antioxidant and anti-cancer effects. However, its role in gastric cancer remains unexplored. This study aimed to investigate the effects of … Garcinone C, a xanthone derived from Garcinia mangostana L, possesses antioxidant and anti-cancer effects. However, its role in gastric cancer remains unexplored. This study aimed to investigate the effects of garcinone C on gastric cancer cell proliferation and its underlying mechanism. We found that garcinone C suppressed gastric cancer cell growth by inducing G0/G1 arrest and apoptosis in a dose-dependent manner. Furthermore, garcinone C downregulated G0/G1 phase markers Cyclin D1 and p21, as well as apoptosis markers Bax, Bcl-2, cleaved-PARP, and c-caspase 3. Following the previous evidence demonstrated that aberrant Hedgehog (Hh) signaling is implicated in gastric cancer development, we confirmed that inhibiting Gli1/2 reduced the growth of AGS and MKN74 cells. Furthermore, garcinone C exerted similar effects to Gant61, inhibiting Hh signaling by reducing Gli1/2 levels and blocking their nuclear translocation. These findings suggest that garcinone C inhibits gastric cancer proliferation via the Hh signaling, indicating its potential as a therapeutic agent for treating gastric cancer.

Hypersynchronous EEG Patterns in a Patient with Holoprosencephaly

2025-05-30

Vishal Pandya , Doris Deng , Siddharth Gupta | Clinical EEG and Neuroscience

Holoprosencephaly is a congenital malformation of the central nervous system resulting from failure of the rostral neural tube to bifurcate into the two cerebral hemispheres. Deep brain structures including the … Holoprosencephaly is a congenital malformation of the central nervous system resulting from failure of the rostral neural tube to bifurcate into the two cerebral hemispheres. Deep brain structures including the thalamus, hypothalamus, and basal ganglia can also be affected to varying degrees. Here we present a patient with a rare de novo pathogenic variant in the PPP1R12A gene and the middle interhemispheric (MIH) variant of holoprosencephaly with hypersynchronous patterns on electroencephalography (EEG). The most prevalent abnormal pattern was abundant hypersynchronous rhythmic theta activity most prominent over the bilateral centro-parietal regions. There was also frequent hypersynchronous rhythmic beta activity and rhythmic alpha range activity, which occurred both synchronously and asynchronously. Finally, there were occasional periods of voltage attenuation interrupting hypersynchronous theta activity. While hypersynchronous theta activity and episodic attenuation have been previously described in alobar and semilobar variants of holoprosencephaly, our report is the first to describe these findings in a patient with the MIH variant as well as the first to describe EEG patterns in a patient with a pathogenic variant in the PPP1R12A gene mutations in which are associated with urogenital and/or brain malformation syndrome. Additionally, the hypersynchronous alpha activity is the first report of such an EEG pattern in holoprosencephaly. In order to develop a more complete understanding of EEG patterns in holoprosencephaly further study is needed but this is challenged by the relative rarity of the disease.

Partial monosomy 18p and 21q due to a paternal reciprocal translocation leading to holoprosencephaly

2025-05-30

Hiroko Wakabayashi , Ayumi Matsumoto , Sakiko Komori +5 more | Human Genome Variation

Abstract Here we report a patient with holoprosencephaly (HPE) associated with 45, XY,der(18)t(18;21)(p11.2;q21.3),-21 derived from a paternal balanced reciprocal translocation. Array comparative genomic hybridization analysis revealed 18p11.32-p11.21 and 21q11.2-q21.3 deletions. … Abstract Here we report a patient with holoprosencephaly (HPE) associated with 45, XY,der(18)t(18;21)(p11.2;q21.3),-21 derived from a paternal balanced reciprocal translocation. Array comparative genomic hybridization analysis revealed 18p11.32-p11.21 and 21q11.2-q21.3 deletions. So far, nine cases of monosomy 18p with an unbalanced translocation (18;21) have been reported, four of which presented with HPE. Our case provides a detailed long-term clinical course and helps us to better understand these rare genetic events.

Wnt/β-catenin regulates Gli1 + osteogenic progenitors in condylar subchondral bone development and osteoarthritis

2025-05-30

Jie Wang , Lin Sun , Yi Zhang +2 more | BMC Musculoskeletal Disorders

Gli1 has been identified as a marker of osteogenic progenitors in the condylar subchondral bone. The Wnt/β-catenin signaling pathway is known to regulate stem cell proliferation and differentiation in bone. … Gli1 has been identified as a marker of osteogenic progenitors in the condylar subchondral bone. The Wnt/β-catenin signaling pathway is known to regulate stem cell proliferation and differentiation in bone. Whether Wnt/β-catenin signaling pathway could influence Gli1 + osteogenic progenitors remains unclear. Here, we aimed to investigate the role and related mechanisms of Wnt/β-catenin signaling in the regulation of Gli1 + osteogenic progenitors in condylar development and temporomandibular joint osteoarthritis (TMJOA). We generated Gli1-CreERT2;tdTomato mice to perform lineage tracing; We generated Gli1-CreERT2; β-cateninfl/fl mice, in which β-catenin was lost in the Gli1 + lineage to examine the role of Wnt/β-catenin signaling pathway in regulating the proliferation and differentiation of Gli1 + cells. The β-catenin CKO mice and their wild-type (WT) littermates were induced at 3 days and were euthanized 1, 2 or 4 weeks after induction; We induced a TMJOA model through a unilateral partial discectomy (UPD) of the temporomandibular joint disc in 6-week-old tamoxifen-treated Gli1-CreERT2;β-cateninfl/fl;tdTomato mice and control group (Gli1-CreERT2;tdTomato mice). We harvested the mandibles at 4 weeks post-surgery. Conditional knockout of β-catenin inhibited the osteogenic activity of Gli1 + progenitor cells during condylar subchondral bone development. In discectomy-induced TMJOA, the overactivation of Gli1 in subchondral bone drove pathological osteogenesis and aberrant subchondral bone remodeling. Deletion of β-catenin in Gli1 + cells mitigated excessive Gli1 + cells activation and ectopic mineralization. Our findings establish Wnt/β-catenin signaling as a key regulator of Gli1 + progenitor cell fate determination in both bone development and TMJOA pathogenesis.

A phase II, open-label study to improve compliance and time of treatment after obtaining complete response (CR) through a tailored schedule of sonidegib in locally advanced basal cell carcinomas (laBCC): The SONIBEC trial.

2025-05-28

Carlo Resteghini , Sara Farinatti , Andrea Alberti +7 more | Journal of Clinical Oncology

9540 Background: Sonidegib is an efficacious treatment of LA laBCC but is associated with a high risk of treatment-related adverse events (TRAEs) causing treatment discontinuation. Following a CR, treatment discontinuation … 9540 Background: Sonidegib is an efficacious treatment of LA laBCC but is associated with a high risk of treatment-related adverse events (TRAEs) causing treatment discontinuation. Following a CR, treatment discontinuation rate reaches up to 60% after a year, leading to 3 years relapse free survival rate of 35%. We aimed at evaluating sonidegib tailored schedule (TS) after CR to increase treatment duration by reducing TRAEs, thus allowing CR maintenance. Methods: We conducted a multicenter, open-label, single-arm phase II study enrolling adult patients (pts) with laBCC who obtained a CR to sonidegib regardless of the tumor’s subtype and burden. Eligible pts received TS1 with sonidegib 14 days on and 14 days off. Pts on TS1 who experienced grade 2-3 toxicity (except alopecia) lasting >28 days moved to TS2 (7 days on and 21 days off). Treatment continued until progression or unacceptable toxicity. Primary endpoint was the rate of pts maintaining sonidegib 12 months after study enrolment (H0 31%, H1 60%). Evaluable pts were defined as all pts who were either on treatment or suspended treatment for reasons other than treatment-unrelated adverse events or death. Secondary endpoints were safety, treatment compliance, rate of disease relapse at 1 and 2 years, overall survival, quality of life, use of concomitant medications and of medical resources, and translational analysis. Results: Between Jan 2021 and Dec 2023, 22 pts from 10 Italian centers were enrolled; the data cut-off was Jan 2025. Pts characteristics are reported in table 1. The median follow-up was 22 months (range 2-33). Three disease and treatment-unrelated deaths occurred before completing 1 year of TS and therefore 19 pts were evaluable. At data cut-off, 12 pts had discontinued treatment: 26% (5) due to disease progression, 11% (2) to sonidegib’s unacceptable toxicity, the remaining either to personal or physician’s choice. Twelve out of 19 evaluable pts (63%) were still on treatment after 1 year from TS start (median duration 20 months, range 2-29), meeting the primary endpoint. The most common TRAEs episodes were muscle cramps (13), alopecia (6), dysgeusia (5) with overall TRAEs grade G1 (29), G2 (11), G3 (3). Twelve pts had dose reduction to TS2. Conclusions: Tailored maintenance schedule with pulsed sonidegib allows for longer treatment duration and fewer relapses in CR laBCC pts. Study follow up to evaluate secondary endpoints outcome and translational analysis are ongoing. Clinical trial information: 2020-002613-17 . Patient characteristics. Characteristic N (%) Male : Female 14 (64) : 8 (36) Median age 76y (range 56-93y) ECOG PS 0-1 15 (68): 7 (32) Histology sub-type Nodular 8 (36) Superficial 2 (9) Infiltrative 7 (32) Mixed 1 (5) Other 4 (18)

Stromal Hedgehog Signaling Is Associated with Favorable Outcomes in Pancreatic Cancer

2025-05-28

Paul Manoukian , Helene Damhofer , Lan Zhao +2 more | International Journal of Molecular Sciences

Aberrant activation of the Hedgehog (Hh) signaling pathway can be observed in various malignancies, particularly in stroma-rich tumors like pancreatic ductal adenocarcinoma (PDAC). In PDAC, Hh signaling is thought to … Aberrant activation of the Hedgehog (Hh) signaling pathway can be observed in various malignancies, particularly in stroma-rich tumors like pancreatic ductal adenocarcinoma (PDAC). In PDAC, Hh signaling is thought to foster an abundant stroma, making it an appealing target for stoma-targeted therapy. However, the use of Hh antagonists in the clinic has thus far not been successful. To reassess the clinical merit of Hh-targeted therapy in PDAC, we sought to better characterize the role of Hh signaling in tumor-stroma crosstalk. Here, we show that Hh ligands are not prognostic per se in PDAC, despite being associated with the favorable classical molecular subtype. Perturbing Hh ligand expression in PDAC cells can effectively alter their trans-signaling capacity but does not impact tumor growth in vivo. However, co-injecting PDAC cells with Smo-proficient MEFs resulted in a significant reduction in xenograft growth, suggesting that Hh-related effects on tumor growth are largely mediated through the stroma. By analyzing transcriptomic sequencing data from co-cultures, comprising human PDAC cells and mouse fibroblasts treated with a Hh-blocking antibody, we could identify stromal hits that are responsive to Hh ligands. We then leveraged the obtained set of genes to allow patient stratification based on stromal response to Hh ligands. We believe that a subset of PDAC patients may benefit from the use of Hh-targeted therapies and thereby encourage the use of our stratification tool to guide their use in PDAC clinical care.

Comparison of the tolerability and safety of hedgehog inhibitors in real-life: A cohort of 330 patients with locally advanced basal cell carcinoma.

2025-05-28

F. Herms , Mourad Djermane , M. Beylot‐Barry +7 more | Journal of Clinical Oncology

9583 Background: Two hedgehog pathway inhibitors (HHIs) have been approved for the treatment of locally advanced basal cell carcinoma (laBCC): vismodegib and sonidegib. Efficacy of both seem similar, even though … 9583 Background: Two hedgehog pathway inhibitors (HHIs) have been approved for the treatment of locally advanced basal cell carcinoma (laBCC): vismodegib and sonidegib. Efficacy of both seem similar, even though no head-to-head comparison has been performed. However, adverse events (AEs) in pivotal trials seemed less frequent with a later onset with sonidegib. CARADERM is a French national database created in 2013 to improve the management of rare skin tumors, including laBCC. The objective of our study was to compare the safety profile of HHIs in this real-life cohort. Methods: LaBCC patients from the CARADERM database were reviewed. Patients who started either vismodegib or sonidegib at least one year before analysis were included. Type and grade of AEs were collected when available. Cumulative incidence of the first occurrence of adverse events was estimated, with treatment discontinuation as a competing event. Results: In the total cohort of 452 laBCC patients, 330 met the inclusion criteria: 280 (85%) treated with vismodegib and 50 (15%) with sonidegib. The median follow-up was 22.3 months. Clinical characteristics (including age, gender, performance status, localization and tumor size) were similar for both groups. The cumulative incidence of the first AE was significantly lower with sonidegib (43.5%, 95% confidence interval (95%CI) = 29.0-57.2 at 12 months) than with vismodegib (63.5%, 95%CI = 57.5-68.9 at 12 months, p=0.0014) (Table 1). For vismodegib treated patients, 191 (68%) experienced at least one AE. The most frequent were cramps (n=123, 44%), dysgeusia (n=123, 44%) and alopecia (n=88, 31%). For sonidegib treated patients, 22 (44%) experienced at least one AE. The most frequent were cramps (n=8, 16%), alopecia (n=7, 14%) and dysgeusia (n=6, 12%). Major AEs seemed to be less frequent and to appear later with sonidegib, with a significant difference for cramps (p=0.007) and dysgeusia (p=0.001), but not significant for alopecia (p=0.059). Conclusions: We present here the largest real-life comparison of HHIs in a real-life cohort of laBCC patients. The cumulative incidence of the first AE was significantly lower with sonidegib. Even though the range of AEs was similar with both HHIs, dysgeusia and cramps were less frequent with sonidegib. These data highlight the difference in terms of tolerance of both HHIs, with a later onset and lower frequencies of AEs with sonidegib. However, though both groups were clinically comparable, vismodegib was overrepresented compared to current prescriptions of HHIs, and further analyses are mandatory to confirm these data. Cumulative incidence of first adverse event at 3, 6 and 12 months. 3 months [95CI] 6 months [95CI] 12 months [95CI] Sonidegib 16.3 % [7.5 ; 28.0] 26.8 % [15.2 ; 39.8] 43.5 % [29.0 ; 57.2] Vismodegib 31.6 % [26.2 ; 37.2] 55.5 % [49.5 ; 61.2] 63.5 % [57.5 ; 68.9] 95CI = 95% confidence interval.

Docking for Smoothened antagonist chemotypes not susceptible to a vismodegib-resistance mutation

2025-05-01

Willem Titulaer , Sebastian Klindert , Corey Taylor +3 more