Extrinsic and intrinsic force regulates cancer progression, aggression and treatment
University of California San Francisco, San Francisco, CA, USA.
All cells experience force and possess mechanosensory mechanisms that enable them to detect mechanical stimuli and transduce these cues into biochemical signals that modify protein function and alter gene expression to influence cellular behavior. Tumors have higher cell and tissue level forces and transformed cells exhibit perturbed mechanosensing. We have been studying the genesis of the altered tumor cell and tissue force and how cells sense and transduce mechanical cues to drive tumor formation and aggression and whether and how this influences treatment response. Using an array of in vitro and in vivo models we found that the ECM progressively stiffens in peripheral tumors such as the breast, skin and pancreas mediated largely by increased collagen deposition, remodeling and crosslinking and induction of fibrosis. Even in tumors such as glioblastomas, which do not exhibit collagenous fibrosis the ECM stiffens due to enhanced hyaluronic acid deposition and proteoglycan crosslinking. We consistently find that a stiffened tumor ECM enhances integrin signaling to promote malignant transformation and tumor aggression that ultimately compromise treatment responsiveness. Consistently, inducing ECM tension or increasing integrin signaling promotes the malignant transformation of pre malignant oncogenically-primed cells and drives the aggressiveness of tumors, whereas inhibiting ECM stiffening prevents tumor progression and reduces aggression. Importantly, when tumor cells are oncogenically transformed or loose expression of critical tumor suppressors they increase their actomyosin tension and enhance their integrin focal adhesion and growth factor receptor signaling. The high tumor cell tension fosters tumor progression and aggression in part by stiffening and remodeling the ECM. The stiff ECM also compromises the tissue vasculature to induce hypoxia and HIF1a to promote a mesenchymal-like frequently metastatic phenotype that is highly resistant to therapy. The stiff ECM also modulates tumor immunity and regulates levels of key repressors that modulate anti-tumor cytotoxic responsiveness.