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

doi:10.1016/j.celrep.2022.111358

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 journal › Article › peer-review

4 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. srGAP1^low 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 srGAP1^low cells remain as solitary disseminated tumor cells in the lungs of mice bearing BC tumors. Overall, srGAP1^low 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 language	English (US)
Article number	111358
Journal	Cell Reports
Volume	40
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2022.111358
State	Published - Sep 20 2022
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

Keywords

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

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10.1016/j.celrep.2022.111358

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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(12), Article 111358. https://doi.org/10.1016/j.celrep.2022.111358

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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 = "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",

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Mondal, C, Gacha-Garay, MJ, Larkin, KA, Adikes, RC, Di Martino, JS, Chien, CC, Fraser, M, Eni-aganga, I, Agullo-Pascual, E, Cialowicz, K, Ozbek, U, Naba, A, Gaitas, A, Fu, TM, Upadhyayula, S, Betzig, E, Matus, DQ, Martin, BL & Bravo-Cordero, JJ 2022, 'A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling', Cell Reports, vol. 40, no. 12, 111358. https://doi.org/10.1016/j.celrep.2022.111358

TY - JOUR

T1 - A proliferative to invasive switch is mediated by srGAP1 downregulation through the activation of TGF-β2 signaling

AU - Mondal, Chandrani

AU - Gacha-Garay, Majo J.

AU - Larkin, Kathryn A.

AU - Adikes, Rebecca C.

AU - Di Martino, Julie S.

AU - Chien, Chen Chi

AU - Fraser, Madison

AU - Eni-aganga, Ireti

AU - Agullo-Pascual, Esperanza

AU - Cialowicz, Katarzyna

AU - Ozbek, Umut

AU - Naba, Alexandra

AU - Gaitas, Angelo

AU - Fu, Tian Ming

AU - Upadhyayula, Srigokul

AU - Betzig, Eric

AU - Matus, David Q.

AU - Martin, Benjamin L.

AU - Bravo-Cordero, Jose Javier

PY - 2022/9/20

Y1 - 2022/9/20

N2 - 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.

AB - 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.

KW - CP: Cancer

KW - TGFβ2

KW - dormancy

KW - extravasation

KW - intravital imaging

KW - invadopodia

KW - lattice light-sheet microscopy

KW - metastasis

KW - quiescence

KW - srGAP1

KW - zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85138154693&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85138154693&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2022.111358

DO - 10.1016/j.celrep.2022.111358

M3 - Article

C2 - 36130489

AN - SCOPUS:85138154693

SN - 2211-1247

VL - 40

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 111358

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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