Abstract A47: Reciprocal dialogue between cellular and extracellular matrix tension and tissue inflammation in pancreatic tumor progression.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profound fibrotic response that contributes to tumor aggression and treatment resistance (Farrow et al., Journal of Surgical Research, 2008). Yet, the molecular mechanisms linking tissue transformation to fibrosis and tumor aggression remain unclear. Tissue fibrosis promotes tissue stiffening and we showed that tissue tension drives transformation and cancer progression, thus we studied the relationship between PDAC progression, fibrosis, and extracellular matrix (ECM) stiffening using KRas transgenic mice (Levental et al., Cell, 2009; Samuel et al., Cancer Cell, 2011). Because inflammation has been casually associated with fibrosis, we combined KRas-induced carcinogenesis with targeted deletion of the TGFβ receptor 2 (TGFβR2KO) which potentiates PDAC aggression through upregulation of Cxc chemokine expression and elevated Stat3 signaling (Ijichi et al., Journal of Clinical Investigation, 2011). Here we report that PDAC progression is accompanied by collagen deposition, reorganization, and LOX-dependent cross-linking that stiffens the ECM and activates focal adhesion kinase (FAK) and that is substantially potentiated through loss of TGFβ receptor 2 signaling. We also noted that the pancreatic epithelium in the TGFβ R2KO mice had higher levels of activated myosin and exerted greater traction forces that enhanced collagen remodeling and contraction. Consistent with a functional link between chemokine signaling and ROCK-dependent cell contractility we showed that the contraction phenotype of TGFβ R2KO pancreatic epithelial cancer cells depends upon Cxcr2 receptor signaling and JAK-ROCK activity (Sanz-Moreno et al., Cancer Cell, 2011). Intriguingly, we also found that Cxc chemokine expression is greatly potentiated by ECM stiffness which feeds forward to enhance Stat3 activation. These findings identify a vicious positive feedback mechanism mediated through ECM remodeling and stiffening that may account for the association between fibrosis, tumor aggression and inflammation in PDACs. This work was supported by the Tumor Microenvironment Network (TMEN) grant NIH/NCI 1U01 CA151925-01 and the Physical Sciences Oncology Center (PSOC) NIH/NCI U54CA143836-01. Citation Format: Hanane Laklai, Raghu Kalluri, Harold Moses, Valerie Weaver, Hideaki Ijichi, Jonathan Lakins, Yekaterina Miroshnikova, Irene Acerbi, Jose Lopez, Elena Kassianidou, Agnieszka Gorska, Sergey Novitskiy. Reciprocal dialogue between cellular and extracellular matrix tension and tissue inflammation in pancreatic tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A47.