In recent decades, the role of tumour biomechanics on cancer cell behaviour at the primary tumour site has been increasingly appreciated. However, the effect of primary tumour biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated.
Our work seeks to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness’s typically found within breast tumours, we have found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonise secondary tissues. Our work has uncovered a metabolic ‘survival switch’ controlled by the stiffness of the primary tumour that can significantly influence how successfully disseminating cells colonise secondary organs
We have shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments, and demonstrated that uncoupling cellular mechanosensing through integrin beta1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. Furthermore, we show that drugs targeting this altered cancer cell metabolism, such as blocking lipid metabolism can ‘starve’ the cancer cells high energy demand and reduce metastasis.
This work is the first to show that softer tumour microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.