PUBLICATION
A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling
- Authors
- Mondal, 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.
- ID
- ZDB-PUB-220922-17
- Date
- 2022
- Source
- Cell Reports 40: 111358 (Journal)
- Registered Authors
- Martin, Benjamin
- Keywords
- CP: Cancer, TGFβ2, dormancy, extravasation, intravital imaging, invadopodia, lattice light-sheet microscopy, metastasis, quiescence, srGAP1, zebrafish
- MeSH Terms
-
- Actins*
- Animals
- Cell Line, Tumor
- Down-Regulation
- Mice
- Transforming Growth Factor beta2*
- Zebrafish
- PubMed
- 36130489 Full text @ Cell Rep.
Citation
Mondal, 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. 40:111358.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping