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Non-canonical Hedgehog signaling via GLI2 promotes pancreatic stellate cell activation and fibrosis in chronic pancreatitis

ABSTRACT: Excessive Hedgehog (Hh) signaling activity contributes to fibrosis in multiple organs, however, its role in pancreatic stellate cell (PSC) activation and fibrosis development during chronic pancreatitis (CP) remains unclear. We demonstrate that GLI2 is upregulated in activated PSCs from CP patients and animal models. Specific deletion of Gli2, but not Smo, significantly alleviated fibrosis in CP models, indicating that CP is driven by non-canonical Hh signaling. Experiments on culture-activated primary PSCs reveal early nuclear translocation and increased GLI2 expression promptly after in vitro culture, with GLI2 being essential for PSC activation. SMO inhibition only reduces GLI2 activation in the short term, while activation of GLI2 by TGF-β/SMAD3 signaling explains the SMO-independent mechanisms leading to Hh activation in PSCs. Altogether, our data demonstrate the activation of the non-canonical Hh pathway in PSCs and indicate that GLI2 represents a promising therapeutic target for CP.

ORGANISM(S): Mus musculus

PROVIDER: GSE281427 | GEO | 2024/11/13

REPOSITORIES: GEO

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Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. mRNA profiling: RNA was prepared from tumours from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Affymetrix Mouse Genome 430 2.0 RNA expression array. The dosage terminology (BID & QD) reflects the dosing schedule, where BID = twice a day, QD = once a day. aCGH: DNA was prepared from tumors from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Agilent mouse CGH 244K Array.

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Non-canonical Hedgehog signaling via GLI2 promotes pancreatic stellate cell activation and fibrosis in chronic pancreatitis

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