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Topic: Christopher Eddy PhD defense: Morphodynamics of 3D Migrating Cancer Cells
Time: Sep 2, 2021 09:00 AM Pacific Time (US and Canada)

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At the intersection of basic science research and clinical relevance, cancer metas- tasis and cell invasion is a multifaceted problem that has been investigated for the past several decades. Importantly, cancer cell plasticity, the ability of a single cell to change its phenotype without genetic mutations in response to environ- mental cues, has confounded clinical progress, and is itself the central investiga- tion of my thesis. Simply put, cell shape is linked to cell function and acts as a holistic measure of cell state. The significance of cell morphodynamics, namely the temporal fluctuation of cell shape, is much less understood. Here we study the morphodynamics of MDA-MB-231 cells in type I collagen extracellular ma- trix (ECM). We show that 3D cancer cell motility is a hidden Markov process whereby the step size distributions of cell migration are coupled with simultane- ous cell morphodynamics. We systematically vary ECM physical properties by tuning collagen concentrations, alignment, and gelation temperatures. We find that morphodynamics of 3D migrating cells are externally controlled by ECM me- chanics and internally modulated by Rho/ROCK-signaling. We employ machine learning to classify cell shape into four different morphological phenotypes, each corresponding to a distinct migration mode. As a result, we map cell morphody- namics at mesoscale into the temporal evolution of morphological phenotypes. We characterize the mesoscale dynamics including occurrence probability, dwell time and transition matrix at varying ECM conditions, which demonstrate the complex phenotype landscape and optimal pathways for phenotype transitions. In light of the mesoscale dynamics, we find that morphological phenotype transitions also facilitate cancer cells to navigate non-uniform ECM such as traversing the inter- face between matrices of two distinct microstructures. Using a tumor organoid model, we show that the distinct invasion potentials of each phenotype modulate the phenotype homeostasis. Overall invasion of a tumor organoid is facilitated by individual cells searching for and committing to phenotypes of higher invasive po- tential. In conclusion, we demonstrate that 3D migrating cancer cells exhibit rich morphodynamics that is controlled by ECM mechanics, Rho/ROCK-signaling, and regulate cell motility. Our results pave the way to the functional understanding and mechanical programming of cell morphodynamics as a route to predict and control 3D cell motility.