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 Jason R Pitarresi A1 Xin Liu A1 Alex Avendano A1 Katie A Thies A1 Gina M Sizemore A1 Anisha M Hammer A1 Blake E Hildreth III A1 David J Wang A1 Sarah A Steck A1 Sydney Donohue A1 Maria C Cuitiño A1 Raleigh D Kladney A1 Thomas A Mace A1 Jonathan J Chang A1 Christina S Ennis A1 Huiqing Li A1 Roger H Reeves A1 Seth Blackshaw A1 Jianying Zhang A1 Lianbo Yu A1 Soledad A Fernandez A1 Wendy L Frankel A1 Mark Bloomston A1 Thomas J Rosol A1 Gregory B Lesinski A1 Stephen F Konieczny A1 Denis C Guttridge A1 Anil K Rustgi A1 Gustavo Leone A1 Jonathan W Song A1 Jinghai Wu A1 Michael C Ostrowski YR 2018 UL https://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.