Cancer cell unjamming and jamming as prerequisite for the formation of primary and metastatic tumors

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Pathological changes such as dysplasia or neoplasia cause morphological changes that induce unjamming as an early motility transition to collectively disseminate cells into the human body. We have recently shown that cancer cell unjamming significantly increases distant metastatic risk. Mechanobiology demonstrates that fibrotic stroma acts as tumor promoter and transforms cells into a more aggressive phenotype that may favor unjamming. According to our recent studies in breast and cervix carcinoma, cancer cell clusters in tumors assume a hybrid state of predominantly soft unjammed cells that form motile regions with an increased tissue fluidity and a few rigid jammed cells that remain in a non-motile state. Together they form a new paradox state of tissues in which a tumor acquires the solid resistance to displace surrounding healthy tissue by cell proliferation and the degrees of freedom as in a fluid to favor cell migration through dense tissues. How unjamming modulates emergent multiscale fluidity, heterogeneity, solid stress in tumor tissue is by far not understood. Recent results particularly indicate that dissemination/nesting of circulating tumor cells may depend on unjamming. We propose a simple microfluidic system that mimics the vasculature of the liver in conjunction with a decellularized tissue matrix to determine the mechanical MRE signature of unjamming and jamming in terms of fluidity, mechanical heterogeneity and solid stress. Cancer cell escape in metastasis may be fostered by unjamming and metastatic nesting by jamming. Our hypothesis is that cancer cell unjamming/jamming transitions are collective cellular biomechanical prerequisites that cancer cells can escape from or nest in the ECM of the liver and pancreas with respect to the vasculature. We will use our recently derived state diagram that uses cell and nucleus shape as well as nucleus number density as variables to microscopically detect jamming/unjamming and correlate it with the according tissue scale MRE signature for cells taken from patient derived pancreas and liver tumors. After setting up our microfluidic assay in work package 1 (WP 1) the packages (WP 2-4) will be pursued in parallel in our microfluidic chamber. We will measure depending on unjamming/jamming: cancer cell aggregation and growth in flows (WP 2), and aggregation/ growth in decellularized ECM under flows (WP 3), and cell dissemination under flow from cell aggregates embedded in decellularized matrix (WP 4). In WP 2-4 we will ultimately use highly heterogeneous primary tumor cells (liver, pancreas) to determine cell phenotypes that favor cancer cell escape and nesting. These measurements will be correlated with table top MRE measurements (WP 5). It is the specific contribution of this subproject to determine the mechanical signatures of cancer cell unjamming/jamming in hepatic and pancreatic tumor formation and metastatic spread.