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A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling
journal contributionposted on 2023-08-22, 21:13 authored by Chandrani Mondal, Majo J Gacha-Garay, Kathryn A Larkin, Rebecca C Adikes, Julie S Di Martino, Chen-Chi Chien, Madison Fraser, Ireti Eni-aganga, Esperanza Agullo-Pascual, Katarzyna Cialowicz, Umut Ozbek, Alexandra NabaAlexandra Naba, Angelo Gaitas, Tian-Ming Fu, Srigokul Upadhyayula, Eric Betzig, David Q Matus, Benjamin L Martin, Jose Javier Bravo-Cordero
Many breast cancer (BC) patients suffer from complications of metastatic disease. To form metastases, cancer cells must become migratory and coordinate both invasive and proliferative programs at distant organs. Here, we identify srGAP1 as a regulator of a proliferative-to-invasive switch in BC cells. High-resolution light-sheet microscopy demonstrates that BC cells can form actin-rich protrusions during extravasation. srGAP1low cells display a motile and invasive phenotype that facilitates their extravasation from blood vessels, as shown in zebrafish and mouse models, while attenuating tumor growth. Interestingly, a population of srGAP1low cells remain as solitary disseminated tumor cells in the lungs of mice bearing BC tumors. Overall, srGAP1low cells have increased Smad2 activation and TGF-β2 secretion, resulting in increased invasion and p27 levels to sustain quiescence. These findings identify srGAP1 as a mediator of a proliferative to invasive phenotypic switch in BC cells in vivo through a TGF-β2-mediated signaling axis.
CitationMondal, C., Gacha-Garay, M. J., Larkin, K. A., Adikes, R. C., Di Martino, J. S., Chien, C. -C., Fraser, M., Eni-aganga, I., Agullo-Pascual, E., Cialowicz, K., Ozbek, U., Naba, A., Gaitas, A., Fu, T. -M., Upadhyayula, S., Betzig, E., Matus, D. Q., Martin, B. L.Bravo-Cordero, J. J. (2022). A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling. Cell Reports, 40(12), 111358-. https://doi.org/10.1016/j.celrep.2022.111358
3101 Biochemistry and Cell Biology31 Biological SciencesBreast CancerCancer2.1 Biological and endogenous factors2 AetiologyActinsAnimalsCell Line, TumorDown-RegulationMiceTransforming Growth Factor beta2ZebrafishCP: CancerTGFβ2dormancyextravasationintravital imaginginvadopodialattice light-sheet microscopymetastasisquiescencesrGAP10601 Biochemistry and Cell Biology1116 Medical Physiology