@article{2146c3481e2d423d9b6853f2c62afa04,
title = "Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth",
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.",
author = "Pitarresi, {Jason R.} and Xin Liu and Alex Avendano and Thies, {Katie A.} and Sizemore, {Gina M.} and Hammer, {Anisha M.} and Hildreth, {Blake E.} and Wang, {David J.} and Steck, {Sarah A.} and Sydney Donohue and Cuiti{\~n}o, {Maria C.} and Kladney, {Raleigh D.} and Mace, {Thomas A.} and Chang, {Jonathan J.} and Ennis, {Christina S.} and Huiqing Li and Reeves, {Roger H.} and Seth Blackshaw and Jianying Zhang and Lianbo Yu and Fernandez, {Soledad A.} and Frankel, {Wendy L.} and Mark Bloomston and Rosol, {Thomas J.} and Lesinski, {Gregory B.} and Konieczny, {Stephen F.} and Guttridge, {Denis C.} and Rustgi, {Anil K.} and Gustavo Leone and Song, {Jonathan W.} and Jinghai Wu and Ostrowski, {Michael C.}",
note = "Funding Information: We acknowledge the Solid Tumor Biology Histology Core Microscopy, Transgenic/Knockout, Target Validation, Analytic Cytometry, Bioinformatics, and Biostatistics Shared Resources. This study was supported by National Institutes of Health grants PO1 CA097189 (MC Ostrowski and G Leone), NRSA F31 CA189757 (JR Pitarresi), NRSA F32 CA221094 (JR Pitarresi), American Cancer Society IRG-67-003-50 (JW Song), American Heart Association 15SDG25480000 (JW Song), and R01 CA124586 (SF Konieczny). This work was also supported by the Department of Defense (W81XWH-14-1-0040, GM Sizemore), Pelotonia Fellowship Program (JR Pitarresi, GM Sizemore, A Avendano, JJ Chang, and CS Ennis), and the OSU Institute for Materials Research. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the Pelotonia Fellowship Program. Publisher Copyright: {\textcopyright} 2018 Pitarresi et al.",
year = "2018",
doi = "10.26508/lsa.201800190",
language = "English (US)",
volume = "1",
journal = "Life Science Alliance",
issn = "2575-1077",
publisher = "Rockefeller University Press",
number = "5",
}