TY - JOUR
T1 - TC10 regulates breast cancer invasion and metastasis by controlling membrane type-1 matrix metalloproteinase at invadopodia
AU - Hülsemann, Maren
AU - Sanchez, Colline
AU - Verkhusha, Polina V.
AU - Des Marais, Vera
AU - Mao, Serena P.H.
AU - Donnelly, Sara K.
AU - Segall, Jeffrey E.
AU - Hodgson, Louis
N1 - Funding Information:
This work was supported by an American Cancer Society Lee National Denim Day Postdoctoral Fellowship [PF-15-135-01-CSM (S.D.)]; NIH grants [CA100324 (J.E.S.), T32GM007288 (S.P.H.M.) and R35GM136226 (L.H.)]. STORM imaging was conducted in the Albert Einstein College of Medicine Analytical Imaging Facility, funded in part by the NCI Cancer Center grant P30CA013330. The Nikon Superresolution microscope (N-STORM imaging system) was purchased with the NIH grant SIG 1S10OD18218-1. Visitron Orbital-200 Ring-TIRF system was purchased with the NIH grant adminis- trative supplement to R35GM136226. J.E.S. is the Betty and Sheldon Feinberg Senior Faculty Scholar in Cancer Research. L.H. is an Irma T. Hirschl Career Scientist. We thank members of the Condeelis, Segall, and Cox laboratories at Albert Einstein College of Medicine for their helpful discussions.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - During breast cancer metastasis, cancer cell invasion is driven by actin-rich protrusions called invadopodia, which mediate the extracellular matrix degradation required for the success of the invasive cascade. In this study, we demonstrate that TC10, a member of a Cdc42 subfamily of p21 small GTPases, regulates the membrane type 1 matrix metalloproteinase (MT1-MMP)-driven extracellular matrix degradation at invadopodia. We show that TC10 is required for the plasma membrane surface exposure of MT1-MMP at these structures. By utilizing our Förster resonance energy transfer (FRET) biosensor, we demonstrate the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates invadopodia-associated TC10 activity and function through the activation of p190RhoGAP and the downstream interacting effector Exo70. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10 GTPase, in breast cancer invasion and metastasis.
AB - During breast cancer metastasis, cancer cell invasion is driven by actin-rich protrusions called invadopodia, which mediate the extracellular matrix degradation required for the success of the invasive cascade. In this study, we demonstrate that TC10, a member of a Cdc42 subfamily of p21 small GTPases, regulates the membrane type 1 matrix metalloproteinase (MT1-MMP)-driven extracellular matrix degradation at invadopodia. We show that TC10 is required for the plasma membrane surface exposure of MT1-MMP at these structures. By utilizing our Förster resonance energy transfer (FRET) biosensor, we demonstrate the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates invadopodia-associated TC10 activity and function through the activation of p190RhoGAP and the downstream interacting effector Exo70. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10 GTPase, in breast cancer invasion and metastasis.
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U2 - 10.1038/s42003-021-02583-3
DO - 10.1038/s42003-021-02583-3
M3 - Article
C2 - 34531530
AN - SCOPUS:85115306923
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1091
ER -
