Invited Talk

Mechanistic and Mechanobiologic Principles of Immune and Cancer Cells 3D Motility Within Mechanically and Structurally Complex Microenvironments

Penn State, College of Medicine, Department of Pharmacology, 1214 Research Boulevard, Hershey, Center for Applied Research, Hummelstown, PA, 17036, USA

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Immune and cancer cells invasion, transmigration and migration through the confining microenvironments of healthy, inflamed or tumor tissues result from the dynamic balance between various canonical and non-canonical migration modes and mechanisms. We decipher septin-enabled mechanism of T cell cortex compartmentalization into a peristaltically-driven amoeboid machinery that features mechanobiologically adaptive T cell circumnavigation through the dense steric obstacles within complex 3D microenvironments. In addition, we show that lymphocytes’ amoeboid motility is complemented and enhanced with a non-canonical dynein-driven contractility within the microtubules network that is crucial for the effective, rupture-free lymphocytes transmigration through the extremely confining microenvironments. We show that lymphocyte passage through the confining lumens is facilitated by the non-stretchable microtubules network that mechanically integrates lymphocytes and ensures an effective, long-distance force transmission along the cell’s axis. Similarly, the dynein-microtubules contractility also powers cancer cells migration, acting alone or in parallel to the actomyosin contractility. We demonstrate that targeting dynein activity modulates cancer cells migration along collagen guidance cues more effectively, than the suppression of the actomyosin contractility, confirmed by the strong correlation between dynein-dynactin dysregulation and the cancer metastatic aggressiveness and poor prognosis. These findings reveal previously unknown cell motility mechanisms and highlight septins, dynein and dynactin as the novel targets for cancer therapy and engineering of the immune response.