RT Journal Article SR Electronic T1 Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800190 DO 10.26508/lsa.201800190 VO 1 IS 5 A1 Pitarresi, Jason R A1 Liu, Xin A1 Avendano, Alex A1 Thies, Katie A A1 Sizemore, Gina M A1 Hammer, Anisha M A1 Hildreth, Blake E A1 Wang, David J A1 Steck, Sarah A A1 Donohue, Sydney A1 Cuitiño, Maria C A1 Kladney, Raleigh D A1 Mace, Thomas A A1 Chang, Jonathan J A1 Ennis, Christina S A1 Li, Huiqing A1 Reeves, Roger H A1 Blackshaw, Seth A1 Zhang, Jianying A1 Yu, Lianbo A1 Fernandez, Soledad A A1 Frankel, Wendy L A1 Bloomston, Mark A1 Rosol, Thomas J A1 Lesinski, Gregory B A1 Konieczny, Stephen F A1 Guttridge, Denis C A1 Rustgi, Anil K A1 Leone, Gustavo A1 Song, Jonathan W A1 Wu, Jinghai A1 Ostrowski, Michael C YR 2018 UL http://www.life-science-alliance.org/content/1/5/e201800190.abstract AB 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.