Poster S13 - Mechanobiological role of dynein in cell organization, motility and immunity

Introduction: The principal cause of death in cancer patients is metastasis, which remains an unresolved problem. Conventionally, metastatic dissemination is linked to actomyosin-driven cell locomotion. However, the locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Thus, the purpose of this study is to investigate the role of microtubules and microtubule-associated motors, particularly dynein, in the migration of cancer cells under conditions of reduced actomyosin contractility. The researchers aim to understand how cancer cells maintain their motility during metastasis when canonical myosin-dependent contractility is compromised. The study also seeks to explore the interplay between dynein and myosin motors in different migration scenarios in two-dimensional (2D) biomimetic collagen networks.

Materials and

Methods: Metastatic and non-metastatic cancer cells motility was studied and mechanistically compared on biomimetic ECM, i.e., collagen lane networks patterned into rhomboid grids to observe the interplay between non-muscle myosin II (NMII) contractility and dynein motricity. The study involves the treatment of MDA-MB-231 and MCF-7 cancer cell lines with various non-muscle myosin II and dynein I inhibitors such as Blebbistatin and Dynarristin respectively to assess the role of dynein-generated forces within the microtubules network in cell migration. The 2D cell migration assay, i.e., live cell imaging, was performed and the morphological, dynamic, and structural responses of the cells were analyzed to cross-compare the effects of myosin and dynein mechanical effects.

Results, Conclusions, and Discussions: The study identified a complementary mechanism of metastatic locomotion powered by dynein-generated forces that emerge within the microtubules. These forces drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers during the absence of myosin contractility while providing enhanced cell structural deformability, suitable for cancer cell invasion into the confining environments of infiltrated solid tissues. Results indicate that the complementary motricity mediated by dynein is always necessary and, in certain instances, sufficient for disseminating metastatic breast cancer cells. These findings advance the fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis.
The study emphasizes the important role of dynein motricity in maintaining cancer cell migration in the absence of conventional contractile forces by introducing novel mechanisms of cell migration. This finding sheds light on potential therapeutic targets for inhibiting metastasis and holds promise in advancing our fight against cancer and offers a fresh perspective on inhibiting its metastatic progression.

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