A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling

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 Naba, Angelo Gaitas, Tian Ming Fu, Srigokul Upadhyayula, Eric Betzig, David Q. Matus, Benjamin L. Martin, Jose Javier Bravo-Cordero

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number111358
JournalCell Reports
Volume40
Issue number12
DOIs
StatePublished - Sep 20 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • CP: Cancer
  • dormancy
  • extravasation
  • intravital imaging
  • invadopodia
  • lattice light-sheet microscopy
  • metastasis
  • quiescence
  • srGAP1
  • TGFβ2
  • zebrafish

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