GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh-Ptch-Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh-Ptch-Smo signaling and is regulated by TGF-b and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells.[Keywords: Pancreatic ductal adenocarcinoma; PDAC; hedgehog; Gli; Smoothened; pancreatic cancer] Supplemental material is available at http://www.genesdev.org.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…For example, it was shown in orthotopic mouse models that hedgehog signaling is required for tumor metastasis of pancreatic cancer ( (Feldmann et al, 2007) and our unpublished data). In contrast, pancreatic-specific deletion of Smo did not affect PDA formation whereas GLI2 expression resulted in undifferentiated pancreatic tumors (Morton et al, 2007;Nolan-Stevaux et al, 2009). These studies indicate that activation of hedgehog signaling is not sufficient for tumor formation of PDAC.…”

“…Recent reports indicate that paracrine hedgehog signaling has an important role in carcinogenesis (Dierks et al, 2007;Yauch et al, 2008;Nolan-Stevaux et al, 2009;Tian et al, 2009). As a recent review has detailed these studies, we will not repeat here.…”

Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis

“…To address whether a paracrine Hh signal is present in autochthonous mouse pancreatic tumors, and to test if tumor epithelium is competent to transduce the Hh signal, we used an oncogenic form of Smo to activate the pathway cell autonomously. This approach was successfully used to study cell-autonomous Hh pathway activation in adult neural stem cells, cerebellum granule cell precursors, and neural crest progenitor differentiation (21, 22, (31). The mechanism by which Hh pathway activation in stromal cells supports tumor growth remains to be established.…”

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

“…Clinically, SHH and its downstream GLI transcription factors, as well as their putative target genes, are expressed in PDA and its precancerous lesion, called pancreatic intraepithelial neoplasia (PanIN) (Berman et al, 2003;Thayer et al, 2003;Prasad et al, 2005). Experimentally, GLI1 was shown to be required for the survival and KRAS-mediated transformed phenotype of PDA cells (Nolan-Stevaux et al, 2009). In a transgenic mouse system, the aberrant expression of a dominant-active form of GLI2 in conjunction with oncogenic KRAS in the pancreatic duct epithelium gave rise to the development of PanIN lesions and PDA (Pasca di Magliano et al, 2006).…”