@article{b380165b2ab04d76a6e27b118ef1b1c0,
title = "A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling",
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.",
keywords = "CP: Cancer, TGFβ2, dormancy, extravasation, intravital imaging, invadopodia, lattice light-sheet microscopy, metastasis, quiescence, srGAP1, zebrafish",
author = "Chandrani Mondal and Gacha-Garay, {Majo J.} and Larkin, {Kathryn A.} and Adikes, {Rebecca C.} and {Di Martino}, {Julie S.} and Chien, {Chen Chi} and Madison Fraser and Ireti Eni-aganga and Esperanza Agullo-Pascual and Katarzyna Cialowicz and Umut Ozbek and Alexandra Naba and Angelo Gaitas and Fu, {Tian Ming} and Srigokul Upadhyayula and Eric Betzig and Matus, {David Q.} and Martin, {Benjamin L.} and Bravo-Cordero, {Jose Javier}",
note = "Funding Information: We would like to thank Young Ah Goo and Shilpa Dilip Kumar for expert advice and services. Multiphoton microscopy was performed in the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai and was supported by ( 1S10RR026639 ). We acknowledge the Microscopy Core and the Flow Cytometry Core from Mount Sinai. We want to thank Ni-Ka Ford for her illustrations. We thank the Aguirre-Ghiso and Sosa laboratories for helpful discussions. We thank Jared A. Rouchard, Colin Morrow, Melanie Freeman, David Parks, Angela Willis, Matthew Grant, and Jenny Hagemeier at the HHMI Janelia Research Campus for zebrafish care and cell culture maintenance. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center , instrumentation award ( S10OD025194 ) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 . C.M. received support from an NIH T32 CA078207 Training Program in Cancer Biology. This work was supported by an NCI Career Transition Award ( K22CA196750 ), an NCI R01 ( CA244780 ) (to J.J.B.-C.), a Damon Runyon-Rachleff Innovation Award ( DDR-47-17 to B.L.M. and D.Q.M), a Stony Brook-Mount Sinai pilot award (to J.J.B.-C., B.L.M., and D.Q.M.) the Pershing Square Sohn Cancer Research Alliance (B.L.M.), and the Tisch Cancer Institute NIH Cancer Center grant ( P30 CA196521 ). Funding Information: We would like to thank Young Ah Goo and Shilpa Dilip Kumar for expert advice and services. Multiphoton microscopy was performed in the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai and was supported by (1S10RR026639). We acknowledge the Microscopy Core and the Flow Cytometry Core from Mount Sinai. We want to thank Ni-Ka Ford for her illustrations. We thank the Aguirre-Ghiso and Sosa laboratories for helpful discussions. We thank Jared A. Rouchard, Colin Morrow, Melanie Freeman, David Parks, Angela Willis, Matthew Grant, and Jenny Hagemeier at the HHMI Janelia Research Campus for zebrafish care and cell culture maintenance. Proteomics services were performed by the Northwestern Proteomics Core Facility, generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center, instrumentation award (S10OD025194) from NIH Office of Director, and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569. C.M. received support from an NIH T32 CA078207 Training Program in Cancer Biology. This work was supported by an NCI Career Transition Award (K22CA196750), an NCI R01 (CA244780) (to J.J.B.-C.), a Damon Runyon-Rachleff Innovation Award (DDR-47-17 to B.L.M. and D.Q.M), a Stony Brook-Mount Sinai pilot award (to J.J.B.-C. B.L.M. and D.Q.M.) the Pershing Square Sohn Cancer Research Alliance (B.L.M.), and the Tisch Cancer Institute NIH Cancer Center grant (P30 CA196521). C.M. designed and performed experiments, analyzed data, and wrote and revised the manuscript. K.A.L. M.J.G.-G. and R.C.A. performed zebrafish embryo experiments. C.-C.C. and A.G. performed atomic force microscopy and data analysis. J.S.Di.M. M.F. and I.E. helped to perform and analyze experiments. E.A.-P. and K.C. assisted with FLIM-FRET experiments. A.N. provided expertise on proteomics. U.O. performed data analysis. B.L.M. and D.Q.M. revised the manuscript for intellectual content. S.U. T.-M.F. and E.B. performed lattice light-sheet/adoptive optics microscopy and data analysis. J.J.B.-C. coordinated the study, contributed to designing and interpretation of the experiments, and wrote and revised the manuscript. A.N. receives research support for work unrelated to this study from Boehringer-Ingelheim. D.Q.M. is a paid consultant for Arcadia Science. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = sep,
day = "20",
doi = "10.1016/j.celrep.2022.111358",
language = "English (US)",
volume = "40",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}