A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-(32 signaling

Many breast cancer (BC) patients suffer from complications of metastatic disease. To form metastases, can-cer 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. srGA-P1low 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-(32 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-(32-mediated signaling axis.

Automated summary

In this study, srGAP1 is identified as a regulator of the proliferative-to-invasive switch in breast cancer cells. srGAP1low cells display a motile and invasive phenotype, facilitating the extravasation of cancer cells from blood vessels and attenuating tumor growth. Interestingly, a population of srGAP1low cells remain as solitary disseminated tumor cells in the lungs.