Extracellular matrix mechanics and its influence on cancer development

The concept that macroscopic tumor stiffness arises from changes in extracellular matrix (ECM) can be been imposed from gathered research data. For example, collagen reorganization leads to an abnormally stiff collagen-enriched stroma. Also, measurements of tissue sections carried out by AFM show regions of higher and lower deformability attributed to stiffness of tumor cells and its environment, respectively. The formation of clinically detectable metastatic sites occurs at the end of stochastic events that allow cells located in the primary tumor site to detach, survive during transition to, and grow in the secondary tumor site. How non-numerous passing cancer cells colonize distant sites knowing that metastasis is a highly inefficient process still remains obscure.

Cellular morphology observed for non-malignant HCV29 (A) and cancerous HT1376 (B) cells cultured on substrates with various stiffness. Images of F-actin were recorded after 24 hours of culture, i.e. in a steady state phase (C). Single-cell spreading area was determined and plotted as a function of substrate stiffness (D). The corresponding changes in cellular deformability describing single cell response to altered mechanical environment (E).

Cancer originates from a single genetically mutated cell capable to proliferate in uncontrolled manner. To form metastasis, the cell first has to detach from the primary tumor site, to invade surrounding extracellular matrix and to pass to lymph or blood circulating systems. In next steps, the cell extravasates and migrates through surrounding tissue to a site where it forms metastasis, i.e. it starts to proliferate again in uncontrolled manner. Mechanically, cancerous cells pass through distinct, actively interacting environment.The last decade has delivered several technological and methodological realizations demonstrating that physical stimuli generated by tumor environment affects cell behavior and properties as profoundly as biochemical signaling. It has been demonstrated that matrix rigidity highly affects tissues homeostasis manifesting in variations in cell morphology, properties and behavior. It has already been demonstrated for various healthy cells like fibroblasts or endothelial cells or even stem cells that cells alter their shape associated with remodeling of actin cytoskeleton in response to stiffness of surrounding environment.In our research we are trying to answer the question to what extent ECM mechanical properties guide cancer cells towards more migratory phenotype.