A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling
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 cell...
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Veröffentlicht in: | Cell reports (Cambridge) 2022-09, Vol.40 (12), p.111358-111358, Article 111358 |
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Sprache: | eng |
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Zusammenfassung: | 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.
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•BC cells can form actin-rich protrusions during extravasation•srGAP1 loss promotes invasion and extravasation while reducing metastatic outgrowth•srGAP1low cells can remain as solitary cells in the lungs of mice with BC tumors•srGAP1 mediates a proliferative-to-invasive switch dependent on TGF-β2 signaling
Disseminated tumor cells can remain quiescent or actively proliferate in distant organs, contributing to aggressive disease. Mondal et al. identify srGAP1 as a regulator of a proliferative-to-invasive decision by breast cancer (BC) cells through a TGF-β2-mediated signaling axis. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2022.111358 |