Figure 1: Tumour cell biophysical adaptations in response to the increase in matrix stiffness during primary tumour development.

As solid tumours grow, invading tumour cells and activated stromal cells remodel the extracellular matrix via an excessive deposition and cross-linking of extracellular matrix proteins such as collagen, fibronectin, and hyaluronic acid. Together, increased matrix deposition and cross-linking result in elevated matrix stiffness. High matrix stiffness induces rapid proliferation of tumour cells and enhances tumour cell stemness and therefore survival. These anti-apoptotic and self-renewal capabilities contribute to increased tumour drug resistance. Elevated matrix stiffness also promotes tumour cell secretion of pro-tumourigenic soluble factors, including matrix-modifying enzymes, pro-angiogenic factors and cytokines. Tumour cells also adapt mechanically to high matrix stiffness by increasing the traction forces exerted on the extracellular matrix, thus resulting in its deformation. Altered force generation further accompanies changes in the deformability of tumour cells in response to elevated matrix stiffness. Moreover, high matrix stiffness primes cancer cells to migrate faster and enhance their invasion into surrounding tissues. We propose that tumour cells that adapt to mechanical stresses in the primary tumour, particularly in response to high matrix stiffness, increase their fitness to successfully navigate the subsequent stresses of the metastatic process.