Abstract SY28-03: The dynamic interplay between extrinsic and intrinsic force regulates cancer progression
Authors: Weaver Valerie M. 
Published: August 2012

All cells experience force and possess mechanosensory mechanisms that enable them to detect mechanical stimuli and transduce these cues into biochemical signals and gene expression changes that influence cellular behavior. Thus embryogenesis, tissue development and homeostasis are all tightly regulated by mechanics and governed by spatially and temporally-regulated tensional homeostasis. By contrast, tumors characteristically exhibit increased tissue level forces across multiple length scales and transformed cells have typically acquired perturbations in mechanosensing. The challenge is to clarify how chemical and mechanical cues collaborate to regulate cellular and tissue level behaviors and to determine when and how these aberrant forces are acquired and if and how they regulate cancer initiation, progression and treatment. The Weaver group has been studying how cells sense and transduce mechanical cues to regulate their behavior and how altered mechanical force compromises tissue homeostasis to drive tumor formation and metastasis and modulate treatment response (reviewed in Butcher et al., Nature Cancer Reviews 2010; Dufort et al., Nature Mol Biol Reviews 2011). Using an array of in vitro and in vivo models we found that the ECM progressively stiffens in an array of tumor types including breast, pancreas, glioblastoma and skin and that ECM tension critically modulates transition to invasion and promotes a metastatic phenotype. We demonstrated that even soft tumors such as aggressive glioblastomas are characterized by a stiffened ECM that is associated with higher levels of ECM proteins that are cross-linked and linearized. We showed that abnormally elevated ECM stiffness compromises morphogenesis and destabilizes tissue architecture largely by promoting the assembly of integrin focal adhesions which potentiate growth factor receptor signaling and induce cytoskeletal remodeling and actomyosin contractility (Paszek et al., Cancer Cell 2005; Paszek et al., PLOS Computational 2009). ECM stiffness potentiates the tumorigenic effects of oncogenes such as Ras, EGFR and ErbB2 by increasing and modifying ERK, wnt and PI3 kinase activity and inducing tissue fibrosis and ECM tension enhances tumor aggression by compromising expression of critical tumor suppressors including PTEN. Consistently, inducing ECM tension promotes the malignant transformation of pre malignant oncogenically-primed epithelial cells, whereas inhibiting ECM stiffening prevents tissue fibrosis and tumor progression (Levental et al., CELL 2009; unpublished findings). ECM tension also regulates tumor metastasis by inducing hypoxic reprogramming and modifying the chemokine microenvironment through pleiotrophic effects on cells of the vascular and immune systems. Finally, and most importantly, we found that when tumor cells are oncogenically transformed or loss expression of critical tumor suppressors per se this corrupts their cellular mechanoresponsiveness and they become hypersensitized or desensitized to extrinsic force and acquire inappropriately elevated cellular tension. Indeed, we could show that oncogenic signaling through Ras to ROCK induces ECM remodeling and stiffening which are necessary for wnt-mediated skin tumor invasion and induction of an epithelial to mesenchymal transition through ECM remodeling and stiffening. Similarly, loss of TGFβ RII in breast and pancreatic tumor cells enhances their contractility to increase chemokine expression thereby fostering tissue inflammation and driving ECM remodeling and stiffening to promote invasion and metastasis. Through collaborations with colleagues at UCSF, Vanderbilt and Harvard the molecular mechanisms and physiological relevance of these observations are being further investigated. Moreover, the clinical relevance of our observations to breast and brain tumors are being explored with colleagues in Oregon, Duke and UCSF. (Supported by DOD BCRP W81XWH-05-1-0330 and NIH U54CA163155-01, 1U01CA151925-01, RO1CA138818-01A1, 2RO1CA085492-11A1, and R01CA140663-01A2 to VMW, NIH 1U01ES019458-01 to ZW and U54CA143836-01 to J.L., NCI P50CA058207 to VMW, CP, LC & SH and KG110560 to S.H. & L.C.).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY28-03. doi:1538-7445.AM2012-SY28-03