TAGLN mediated stiffness-regulated ovarian cancer progression via RhoA/ROCK pathway

Background: Ovarian cancer (OC) progression is an unmet medical challenge. Since omental metastases were palpated harder than their primary counterparts during cytoreductive surgery of patients with epithelial ovarian cancer, we were inspired to investigate OC progression from the perspective of biomechanics. Methods: Atomic Force Microscope (AFM) was used to measure the young’s moduli of tissues. The collagen-coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The effect of TAGLN were evaluated both in vitro and in vivo using transwell, immunofluorescence, western blot analysis and immunohistochemistry. Findings: We quantitatively confirmed that omental metastases were stiffer and more abundant in desmoplasia compared with paired primary tumors, and further demonstrated that matrix stiffness could notably regulate OC progression. Remarkably, TAGLN, encoding an actin cross-linking/gelling protein, was identified as a potent mechanosensitive gene that could form a regulation loop with Src activation reacting to environmental stiffness, thus mediating stiffness-regulated OC progression through regulating RhoA/ROCK pathway. Interpretation: These data demonstrate that targeting extra-cellular matrix stiffness could probably hamper OC progression, and of note, targeting TAGLN might provide promising clinical therapeutic value for OC therapy. Funding: This work was supported by the “973” Program of China (No. 2015CB553903 to Ding Ma and Junbo Hu), Technical Innovation Special Project of Hubei Province (2018ACA138), the Fundamental Research Funds for the Central Universities (2019kfyXMBZ024), National Science and Technology Major Sub- Project (2018ZX10301402-002), and the National Science Foundation of China (81902661, 81772787, 82072889). Declaration of Interest: None to declare. Ethical Approval: Human ovarian cancer tissues were all obtained from patients undergoing surgery at the Department of Obstetrics and Gynecology, Tongji Hospital, Huazhong University of Science and Technology after obtaining written informed consent of the patients and the authorization of the Ethics Committee of Tongji Hospital (TJ-iRB20181103). Fresh tissues were prepared for the Atomic Force Microscope (AFM) measurement, frozen or formalin fixed.