Introduction: The role of the extracellular matrix (ECM) as a critical regulator of cancer cell behavior and tumour progression is becoming increasingly recognized. Several studies have established clear roles for the ECM in the metastatic progression of cancer. Despite this, we do not fully understand the precise underlying mechanisms regulated by different ECM components, nor how the mechanical properties conferred by them alters both healthy and diseased tissues.
Methods: Here we investigate the role of substrate stiffness and ECM composition on Triple Negative Breast Cancer (TNBC) behavior both in vitro and in vivo using functionalized tunable stiffness polyacrylamide gels mimicking healthy and tumour tissues. Pre-conditioning on variable stiffness substrates, was coupled with multiplexed systems analysis of intracellular rewiring, and functional validation of in vivo metastasis forming ability.
Results: In vitro characterization of TNBC cells showed stiffness dependent changes in proliferative capacity through rewiring of intracellular signaling pathways. These changes led to an altered window of opportunity whereupon in vivo, rewiring of signaling pathways alters metastatic colonization ability in a secondary organ-specific manner.
Discussion: By uncoupling substrate stiffness from ECM composition, we can better understand the precise role of mechanical pre-conditioning of cancer cells and interrogate the longevity of subsequent intracellular re-wiring. Our results suggest that substrate stiffness and ECM composition likely play significant and opposing roles in the different stages of cancer metastasis with further work needed to fully understand the therapeutic potential of targeted ECM manipulation in the treatment of metastatic cancer.