Abstract
The contribution of the tumor microenvironment to pancreatic ductal adenocarcinoma (PDAC) development is currently unclear. We therefore examined the consequences of disrupting paracrine Hedgehog (HH) signaling in PDAC stroma. Herein, we show that ablation of the key HH signaling gene Smoothened (Smo) in stromal fibroblasts led to increased proliferation of pancreatic tumor cells. Furthermore, Smo deletion resulted in proteasomal degradation of the tumor suppressor PTEN and activation of oncogenic protein kinase B (AKT) in fibroblasts. An unbiased proteomic screen identified RNF5 as a novel E3 ubiquitin ligase responsible for degradation of phosphatase and tensin homolog (PTEN) in Smo-null fibroblasts. Ring Finger Protein 5 (Rnf5) knockdown or pharmacological inhibition of glycogen synthase kinase 3β (GSKβ), the kinase that marks PTEN for ubiquitination, rescued PTEN levels and reversed the oncogenic phenotype, identifying a new node of PTEN regulation. In PDAC patients, low stromal PTEN correlated with reduced overall survival. Mechanistically, PTEN loss decreased hydraulic permeability of the extracellular matrix, which was reversed by hyaluronidase treatment. These results define non-cell autonomous tumor-promoting mechanisms activated by disruption of the HH/PTEN axis and identifies new targets for restoring stromal tumor-suppressive functions.
Highlights
The most prominent histopathological hallmark of pancreatic cancer is its uniquely dense tumor stroma, comprised activated fibroblasts, immune cell infiltrates, abnormal angiogenesis, and extracellular matrix (ECM) (Feig et al, 2012)
We have identified a mechanism by which stromal fibroblasts promote pancreatic tumor cell growth
HH signaling has been shown to act in a paracrine manner in pancreatic ductal carcinoma (PDAC), with tumor-secreted sonic hedgehog (SHH) activating the HH pathway in pancreatic fibroblasts (Yauch et al, 2008).These studies, did not directly address the potential oncogenic functions of the tumor microenvironment in pancreatic cancer progression
Summary
The most prominent histopathological hallmark of pancreatic cancer is its uniquely dense tumor stroma, comprised activated fibroblasts, immune cell infiltrates, abnormal angiogenesis, and extracellular matrix (ECM) (Feig et al, 2012). The stroma undergoes a dramatic expansion in concert with the step-wise development of pancreatic ductal carcinoma (PDAC), suggesting that the stroma is an active partner in PDAC initiation and progression (Feig et al, 2012) In support of this view, a cohort of patients with tumors exhibiting a higher content of smooth-muscle actin (SMA)–positive cells had significantly reduced overall survival compared with individuals with fewer of these cells (Fujita et al, 2010). Ablation of SHH ligand in tumor cells was shown to decrease stromal activation and increase tumor cell growth (Lee et al, 2014; Rhim et al, 2014) Consistent with these results, work from our group demonstrated that deletion of the key HH signaling effector Smoothened (Smo) from SMA-positive fibroblasts led to an increase in pre-neoplastic acinar-to-ductal metaplasia (ADM) (Liu et al, 2016). The mechanism involved activation of a non-canonical AKT/GLI2 oncogenic pathway, production of TGF-α by fibroblasts, and activation of epidermal growth factor receptor signaling in epithelial cells (Liu et al, 2016)
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