Abstract:

Extracellular vesicles (EVs) are membrane-bound vesicles secreted by cells. EVs can alter biological processes in recipient cells. EV biogenesis occurs both intracellularly within the endosomal pathway, generating exosomes, and at the plasma membrane, producing ectosomes. EV-mediated intercellular communication drives several cancer hallmarks. Tumors also leverage dysregulated extracellular matrix (ECM) remodeling to create a conducive microenvironment. The primary focus of my research is to delineate the intricate interplay between EVs and remodeled ECM in solid tumors.

ECM remodeling comprises both mechanical (such as ECM stiffening) and chemical (such as deposition of hyaluronic acid) changes. Our analysis of a pan-cancer mechanobiology dataset indicates substantial heterogeneity in how cell mechanics changes within and across tissue types in response to mechanosensitive and chemosensitive changes in ECM. Using unsupervised machine learning, we identified phenotypic classes that characterize the physical plasticity, i.e. the distribution of physical feature values attainable, of a particular cell type in response to different ECM-based conditions.

Using a continuum mesoscale membrane model, we show that the tendency for curvature generation (needed for vesiculation) by curvature-inducing proteins has an ultrasensitive dependence on cortical tension. Based on the heterogeneous response observed in the pan-cancer mechanobiology dataset, cancer cells may respond to increased ECM stiffness through reduction in cortical tension, which can then potentiate vesiculation. We thus propose a two-pronged mechano-regulation of exosome production in cancer cells, consisting of the effect of ECM stiffness, mediated by cortical tension, in modulating vesicle biogenesis and the previously identified mechanotransduction signaling axis (Akt-Rabin8-Rab8) regulating endosomal transport to plasma membrane for exosome secretion. Predictions of change in exosome secretion as the matrix stiffens based on this framework compare well with experimental measurements for primary hepatocytes and hepatocellular carcinoma cells. This study thus highlights how exosome production might be (de)regulated in tumors by mechanobiology-based mechanisms.

Zoom Information:
Meeting ID: 953 3127 5933
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