Poster #104, Sanford Burnham Prebys Medical Discovery Institute
Matrix stiffness activates FAK in high-grade serous ovarian cancer cells
Mentors: Isabel Sakowicz, BSc and Kevin Tharp, PhD
High-grade serous ovarian cancer (HGSOC) is the most common and lethal form of ovarian cancer. Focal adhesion kinase (FAK) is often overexpressed in HGSOC and used by tumor cells to survive platinum-based chemotherapies. FAK is a non-receptor tyrosine kinase activated through integrin receptors’ binding to extracellular matrix (ECM) protein. FAK translates mechanical forces into intracellular signaling and its activation and downstream signaling drive cell migration, proliferation, and chemoresistance. The function of FAK is important in tumor formation as its activation status positively correlates with ovarian cancer invasiveness and negatively affects patient survival. We hypothesize that increased ECM stiffness in the tumor environment activates FAK in HGSOC cells. This study investigated how ECM substrate properties, such as stiffness and viscoelasticity, affect FAK activation and subsequent cellular behavior. To examine FAK’s mechanosensitivity in native physiological properties of the tissue microenvironment, bioengineered hydrogels of increasing stiffness were employed to mimic in vivo ECM of the mouse peritoneum (4kPa), fibrotic peritoneum (22 kPa), “soft” tumor (60 kPa), and stiff tumor (150 kPa). We found that phospho-FAK (Tyr397) was significantly elevated on the cell membrane at 150 kPa compared to 4 kPa (p < 0.0001), while intermediate stiffnesses (22 kPa, 60 kPa) did not differ significantly from the softest condition. This suggests that FAK is activated by ECM stiffness found in a stiff tumor, while lower stiffness found in normal tissue and “soft” tumor does not activate FAK. In conclusion, our results suggest that ECM stiffness is a key driver of FAK activation, providing a mechanistic link between the biomechanical tumor microenvironment and the migratory, proliferative, and chemoresistant phenotypes characteristic of HGSOC progression. Targeting FAK mechanosensitivity may consequently offer a promising therapeutic strategy for disrupting tumor-ECM crosstalk in ovarian cancer.