Shear stress alters mito-cytoskeletal dynamics and mobilizes mechanosensitive transcription factors supporting a chemoresistant phenotype in ovarian cancer cells

Abstract Ovarian cancer remains one of the most lethal gynecological malignancies, largely due to the frequent development of resistance to platinum-based chemotherapies such as cisplatin (cisPt). Emerging evidence supports that the biophysical properties of the tumor microenvironment (TME) play a pivotal role in shaping chemoresistance. Shear stress (SS) within the ovarian cancer TME influences cancer cell behavior by modulating cytoskeletal organization and mechanosensitive transcription factors activation. Supporting tumor progression, transcription factors translate mechanical cues from the extracellular matrix into transcriptional programs to enhance tumor growth, metastatic spread and drug inefficacy. To this, mechanical stress within the TME can directly impact mitochondrial morphology and bioenergetic capacity, thereby reinforcing cisPt resistance. Here we have identified mitophagy as a key molecular event linking the extracellular physical cues, namely exposure to shear stress, to a reduced cisPt activity in ovarian cancer cells. This process involves cytoskeletal adjustment, SS-induced nuclear translocation of transcription factors supporting antioxidant defense and mitochondrial turnover such as Nrf2, PGC1α and Klf2/4. When application of SS triggered a reduction of mitochondrial mass, this was accompanied by chemoresistance, similar to chemically induced mitophagy. In turn, application of autophagy inhibitor bafilomycin increased the sensitivity of SKOV3 ovarian cancer cells. This integrative perspective paves the way to grasp molecular mechanisms relevant for chemoresistance in vivo and opens new opportunities to resolve therapeutic vulnerabilities by targeting mechanotransduction pathways or mitochondrial dynamics to restore cisPt sensitivity.