Research Of Ovarian Cancer Progression Based On Biomechanics

Objective: This study aimed to determine the stiffness of primary sites and omentum metastases of advanced serous ovarian cancer,further study the role of mechanical cues in the progression of ovarian cancer and revealed the main regulatory mechanism.Importantly,we explored whether inhibition of tumor stiffness restrained ovarian cancer progression,thus providing new therapeutic strategy for ovarian cancer therapy.Methods: We utilized Atomic Force Microscope(AFM)to detect the Young's Modulus of primary sites and omentum metastases of advanced serous ovarian cancer.Polyacrylamide(PA)gels were fabricated to mimic substrates with various stiffness,investigating the cellular behaviors of cells cultured on substrates with various stiffness.Transcriptomic Array was used to screen the pivotal gene that regulated by tissue mechanics.?-aminopropionitrile(BAPN)was used to inhibit the stiffness of ovarian cancer and to observe the change of ovarian cancer progression.Results: The Young' Modulus of eight paired primary sites and omentum metastases of advanced serous ovarian cancer were detected by AFM and we found that the omentum metastases were significantly stiffer than primary sites.Through analyzing the expression of collagen and Lysyl oxidase(LOX)of paired ovarian cancer,we indicated that omentum metastases exhibited desmoplasia compared to primary sites.We further determined that the capability of migration,invasion and proliferation of ovarian cancer cells were significantly stronger when cells grown on stiff substrates,compared to cultured on soft substrates.Transcriptomic Array identified TAGLN as a mechanoresponsive gene,played a crucial role in stiffness-related ovarian cancer progression,and could also sense cytoskeleton tension.Specifically,we found that TAGLN exerted interplay with Src and this regulatory loop played a crucial role in ovarian cancer progression.Notably,inhibition of ECM stiffness with BAPN significantly impaired ovarian cancer metastasis.Conclusion: We found that omentum metastases of ovarian cancer were stiffer and exerted significantly desmoplasia compared to primary sites of advanced serous ovarian cancer.Moreover,we demonstrated that tissue mechanics regulated malignant behaviors of ovarian cancer cells.Mechanistically,we found the regulatory loop between Src and TAGLN played crucial role in ovarian cancer progression.Importantly,inhibition of ECM stiffness significantly impaired ovarian cancer metastasis.Thus,our work suggests the pivotal role of mechanical cues in ovarian cancer progression and suggesting therapeutically targeting tumor stiffness may help attenuate ovarian cancer metastasis.