Mechanoregulation of Metastasis beyond the Matrix

Abstract

Epithelial transformation and carcinogenesis are characterized by profound alterations in cell mechanics that significantly affect multiple steps of the metastatic cascade. The ability of cancer cells to grow in the primary tumor, to locally invade through the confining extracellular matrix, to survive in circulation, and to extravasate into distant vital organs all depend on specific mechanical characteristics. Importantly, recent studies have shown that the mechanical properties of cancer cells also influence their interactions with immune and stromal cells. Here, we discuss the mechanical changes that cancer cells undergo during metastasis, how these changes affect immune and stromal responses, and the implications of these new insights for therapeutic intervention.

Figure 1.

Changes in mechanical and biophysical properties of epithelial cells (blue font) start at the precancerous stage and dynamically take place throughout from tumorigenesis to metastasis. Several components of the tumor microenvironment such as the fibroblasts, macrophages, and the ECM contribute to these changes.

Figure 2.

Beyond the matrix, biophysical forces generated by laminar flow and loss of substrate attachment dictate the metastatic fate by affecting several processes such as resistance to anoikis, entosis, catch bond formation, clustering, extravasation, and the immune response.

Figure 3.

Once in secondary organs, DCCs engage signaling and mechanotransduction to activate transcription factors such as YAP and MRTF for overt outgrowth. However, mechanotransduction, F-actin cytoskeleton remodeling, and the associated changes in cortical stiffness of DCCs expose them to mechanosurveillance by cytotoxic lymphocytes. Cytotoxic lymphocytes' recognition of cancer cells’ cortical stiffness triggers force exertion and amplifies their own mechanotransduction for increased cytotoxicity through lytic granule and cytokine secretion. This paradox severely affects metastatic progression and it partly explains why the metastatic cascade is extremely inefficient, with less than 1% of the disseminated cancer cells successfully colonizing distant organs.