Pancreatic cancer gEnotypE adjusts fiBrotic phEnotypE to drivE pancrEatic cancEr

Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis, which can either promote tumor progression by physically preventing chemotherapy drugs and immune cells from targeting tumor cells, or inhibit tumor progression by decreasing tumor cell invasion. Elucidation of the relationship between tumor genotype and fibrotic phenotype could identify the PDACs that would benefit from stroma-targeting therapies, such as mesenchymal-like PDACs, which are highly fibrotic, frequently exhibit compromised TGFβ signaling, and are more resistant to treatment than classic PDAC. Laklai and colleagues characterized the fibrotic phenotypes of different PDAC genotypes and found that collagen thickness may be associated with tumor cell tension, and that both were linked to PDAC prognosis. Similarly, PDACs that exhibited decreased TGFβ signaling or mutant SMAD4 had thickened collagen bundles, which were shown to be stiffer in PDACs harboring mutant SMAD4 by atomic force microscopy. Examination of transgenic mouse models of PDAC revealed that although PDACs driven by mutant Kras and either deletion of Tgfbr2 (KTC) or Tp53 (KPC) had similar levels of collagen and other stromal components, KTC tumors had thicker collagen bundles. KTC tumor cells exhibited Rho kinase 1 (ROCK1)–dependent tumor growth, increased tumor cell tension, and a stiffer fibrotic phenotype compared to KPC or mutant Kras (KC) tumors. Transgenic mouse models of increased b1-integin–driven cell tension exhibited enhanced STAT3 activation and increased PTK2associated focal adhesion signaling, extracellular matrix (ECM) stiffening, and fibrosis in pancreatic epithelial cells of nontumor mice, and drove ECM remodeling and stiffening, increased fibrosis, and accelerated PDAC progression in KC mice. Consistent with these findings, constitutively activated STAT3 induced fibrosis and quickened PDAC progression. Inhibition of JAK or PTK2 reduced matricellular fibrosis, ECM stiffness, and PDAC development. Together, these results describe a positive feedback loop between tumor cell tension, driven by PDAC genotype-induced mechanosignaling, and fibrosis that promotes tumor progression and aggression. n