UC San Diego

The high mortality rate of cancer is associated with metastasis of the primary tumor and can drastically reduce a patient’s 5-year survival rate. Patient outcomes typically scale with the rate of cell dissemination from the primary tumor, but the lack of a universal molecular prognostic marker and cell heterogeneity within the tumor complicate calibrating patient care. Even though there is limited overlap in the genetic mutations and biochemical changes that arise in specific cancer types, all solid tumor cells must detach, migrate, and invade the surrounding tissue in order to metastasize. The cell mechanotype and its effect on cell-ECM dynamics plays an important role in this process, and offers a more conserved feature across the variety of different cancers. This dissertation aims to utilize these characteristics – specifically adhesion strength between the cell and the extracellular matrix – to assess the metastatic risk of a given cancer cell population. We first examined how heterogeneity in cell-ECM adhesion strength within an isogenic population of cancer cells could present intrapopulation differences in metastatic ability. Weakly adherent cells from a number of different cancer types consistently displayed greater migration speeds in vitro compared to their strongly adherent counterparts. Biophysical modeling and experimental validation suggest that differences in intra-cellular actomyosin activity are the proximate driver for differences in migration speed, rigidity sensing, and durotactic behavior. Using a murine mammary tumor model, we then demonstrated the prognostic capabilities of a divergent parallel-plate flow chamber to measure the adhesion strength and cancer cell percentage of tumor and stromal biopsies, and found that less adherent cancer cells generate more secondary metastases. Taken together, these studies demonstrate the utility of using adhesion strength as a biophysical marker to predict metastatic risk. Our microfluidic device that utilizes shear to measure adhesion strength may provide the means to accurately assess the metastatic potential of a patient’s primary tumor and better inform treatment options.