Abstract IA09: Extrinsic and intrinsic force regulate cancer progression and aggression

Abstract

Abstract Cells experience force and possess mechanotransduction machinery to detect physical cues from their microenvironment and to transduce and biochemically amplify these signals to modulate their differentiation, growth, survival, migration and morphogenesis. Tumors show increased tissue level forces and transformed cells exhibit a perturbed mechanophenotype. We have been studying how cells transduce mechanical cues to regulate their fate and how altered force compromises tissue homeostasis to drive malignancy and metastasis. We found that the ECM in breast, pancreas, skin and glioblastomas is remodeled during malignancy such that the ECM stiffens as a function of tumor progression and aggression. A stiffened ECM compromises tissue differentiation by promoting integrin focal adhesion (FA) assembly that potentiates transmembrane receptor signaling and induces cytoskeletal remodeling and actomyosin contractility. Our findings indicate that high mechanosignaling collaborates with oncogenes including Ras and ErbB2 and reduces the levels of key tumor suppressors including PTEN and BRCA1 to drive transformation. By this means an increase in ECM stiffness promotes the malignant transformation of pre malignant cells and drives tumor cell metastasis, and inhibiting ECM stiffening restores tumor suppressor function and reduces oncogenic signaling to prevent malignancy. We determined that these effects are linked to the cells ability to “tune” their actomyosin tension to the stiffness of their surrounding microenvironment which induces focal adhesion assembly through a vicious feed-forward mechanism. The elevated cell contractility and increase in focal adhesions modifies cell signaling through RhoGTPases modify ERK, PI3 kinase, Myc and Wnt signaling to amplify proliferation and survival, and invasion, to increase the level of factors such as VEGF that drives angiogenesis, to stimulate cytokine and chemokine expression that fosters inflammation and to induce hypoxic reprogramming to drive tumor metastasis and compromise therapeutic efficacy. Interestingly, we showed that oncogenic transformation and the loss of key tumor suppressors per se also elevate cell intrinsic tension and drive tumor progression and aggression by inducing ECM remodeling and stiffening to elevate mechanosignaling. Indeed, we could show that the cancer cells genotype “tunes” the stromal response of the tissue and influences tumor aggression in part by modifying tissue tension. We will present evidence to support a role for both intrinsic and extrinsic mechanical force in solid tumors and discuss how these findings could provide insight to guide and improve cancer therapy (Supported by DOD BCRP BC122990 to VMW, NIH NCI R01CA192914 to VMW, 5 R01 CA085492-11A1 to VMW and HM, 1U54CA163155-01 to VMW and GB, R01CA174929 to VMW and CP, R33 CA183685-01 to VMW and KH and 1U01CA202241-01 to VMW and JG.) Citation Format: Valerie Weaver. Extrinsic and intrinsic force regulate cancer progression and aggression. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr IA09.