Tissue fluidification in pathophysiology - Giorgio Scita (IFOM, FIRC Institute of Molecular Oncology & Department of Oncology and Hemato-oncology, University of Milan)

The process in which locally confined epithelial malignancies progressively evolve to become invasive cancer cells is associated with the acquisition of cell motility, fostered by a mechanical shift from a solid-like to a liquid-like state, known as unjamming. The biomolecular machinery behind unjamming has only begun to be unraveled, while whether the perturbations associated with this tissue-level mechanical transition impact on phenotypes during carcinoma progression remains unclear. Using a combination of physical approaches, ex vivo and in vivo model systems, we will address these issues and discuss whether an endocytic-driven transition between “solid” and “liquid” states of cell collectives is a complementary gateway to cell migration in pathology, focusing specifically on the progression of early breast cancer lesions that become locally invasive. We will show how these dynamics changes featuring the coexistence of long-range coordinated motion and local cell re-arrangement are sufficient to promote matrix remodeling, and xlocal invasion and exert mechanical stress on individual cell nuclei. This is accompaniedby profound transcriptional rewiring, with the unexpected activation of an inflammatory response, change in cell state, and the emergence of malignant traits.