Abstract LB-143: Interplay between tissue tension and inflammation in pancreatic tumor progression
Authors: Laklai Hanane , Miroshnikova Yekaterina , lakins Jon , Sergey Novitskiy , Gorska Agnes , Korets Lidiya , Kalluri Raghu , Moses Harold , Weaver Valerie 
Published: May 2015

Pancreatic ductal adenocarcinoma (PDAC) is amongst the most lethal malignancies due largely to an inability to detect these tumors early and thereafter a lack of effective therapies for late stage cancers (Tempero, 2003). PDAC is characterized by a strong desmoplastic response including significant extracellular matrix (ECM) remodeling that severely compromises treatment and surgical resection (Farrow, 2008). Nevertheless, the molecular mechanisms linking tissue transformation to fibrosis and tumor aggression remain unclear. Tissue fibrosis increases tissue tension and we showed that ECM stiffness and epithelial cell tension drive squamous carcinoma and mammary transformation (Levental, 2009; Samuel, 2011). We therefore asked whether pancreatic fibrosis promotes PDAC progression and aggression by increasing ECM stiffness and tissue tension and how. Inflammation is casually-associated with fibrosis and targeted deletion of the TGFβ receptor 2 (TGFβR2KO) when combined with expression of KRas up regulates CXC chemokine expression to promote PDAC aggression (Ijichi, 2011). Here we report that PDAC progression is accompanied by significant fibrosis and inflammation that correlated strongly with collagen deposition and LOX-dependent cross-linking and ECM stiffening. PDAC progression associated with elevated CXC chemokine levels as well as high epithelial STAT3 activity and elevated mechanosignaling in the epithelium including activated myosin, FAK and YAP and enhanced PDAC contractility. Intriguingly, we showed that PDAC contractility is functionally linked through a reciprocal Cxcr2 receptor - GPCR- JAK-STAT3 - ROCK - FAK signaling circuit that contributes to PDAC aggression and tissue inflammation. Consistently, the pancreas of mice expressing a targeted β1 integrin V737lox/lox clustering mutant, which drives integrin-dependent mechanosignaling in their epithelium showed profound fibrosis, high pSTAT3 and chronic inflammation which progressed to pancreatitis by as early as 3 months of age when combined with the KRas oncogene. Ongoing studies are currently exploring the relevance of Stat3 on pancreatic fibrosis and tumor aggression. Nevertheless, our findings identify a vicious positive feedback mechanism mediated through tissue tension that may account for the strong association between fibrosis, tumor aggression and inflammation in PDAC. (This work was supported by the Tumor Microenvironment Network (TMEN) grant NIH/NCI 1U01 CA151925-01, the Pancreatic Cancer Action Network-AACR Innovative Grant 30-60-25-WEAV, and NIH/NCI R01 CA138818-01A1 to VMW).

Citation Format: Hanane Laklai, Yekaterina Miroshnikova, Jon lakins, Novitskiy Sergey, Agnes Gorska, Lidiya Korets, Raghu Kalluri, Harold Moses, Valerie Weaver. Interplay between tissue tension and inflammation in pancreatic tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-143. doi:10.1158/1538-7445.AM2014-LB-143