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Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE156867 | GEO | 2021/02/01

REPOSITORIES: GEO

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Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [scRNA-seq]

Project description:A better understanding of the roles of signaling pathways differentially activated in distinct fibroblast populations will shed light on the complexity of fibroblast heterogeneity in pancreatic cancer. Here, we show that Hedgehog pathway inhibition alters the fibroblast composition towards a more inflammatory microenvironment, opening the possibility for future combination therapies.

2021-02-01 | GSE156438 | GEO

Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [bulk RNA-seq]

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Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer

Project description:Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer

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Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.

Project description:PurposePancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.Experimental designWe used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.ResultsWe found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.ConclusionsHedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

| S-EPMC8026631 | biostudies-literature

Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [scRNA-seq]

Project description:Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [scRNA-seq]

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Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [bulk RNA-seq]

Project description:Hedgehog signaling alters the balance of fibroblast subtypes in pancreatic cancer [bulk RNA-seq]

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Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-12-05 | GSE246459 | GEO

Molecular subtypes in pancreatic adenocarcinoma

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-06-01 | E-GEOD-77859 | biostudies-arrayexpress

Stromal response to Hedgehog signaling restrains pancreatic cancer progression.

Project description:Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

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Molecular subtypes in pancreatic adenocarcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-06-01 | GSE77859 | GEO