A Proliferative to Invasive Switch is Mediated by srGAP1 Downregulation Through the Activation of TGFβ2 Signaling

Abstract

Many breast cancer (BC) patients suffer from complications of metastatic disease. In order to extravasate efficiently and form metastasis, cancer cells have to become migratory and coordinate both invasive and proliferative programs at distant organs. Here, we identify srGAP1 as a regulator of the proliferative-to-invasive switch in BC cells. Highresolution adaptive optics/light sheet microscopy demonstrates that BC cells form actinrich protrusions to contact and cross the endothelial layer during extravasation. srGAP1 low cells display a highly 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 (DTCs) in the lungs of mice bearing BC tumors. Furthermore, multiphoton imaging with BC cells expressing a Cdk2 biosensor show that srGAP1 low cells enter into a G0/G1 state and remain as single cells or small clusters in the lungs. Finally, RNAseq and secretome analyses reveal that srGAP1low cells have increased Smad2 activation and TGFβ2 secretion, resulting in an increase in both invasion and p27 levels to sustain quiescence. These findings describe a novel mechanism mediating the shift from a proliferative to an invasive phenotype in BC cells in vivo and identify srGAP1 as a mediator of this phenotypic switch through a TGFβ2 signaling axis.