TC10 regulates breast cancer invasion and metastasis by controlling membrane type-1 matrix metalloproteinase at invadopodia

• Published in: Communications biology 2021-09, Vol.4 (1), p.1091-1091, Article 1091
• Main Authors: Hülsemann, Maren, Sanchez, Colline, Verkhusha, Polina V., Des Marais, Vera, Mao, Serena P. H., Donnelly, Sara K., Segall, Jeffrey E., Hodgson, Louis
• Format: Article
• Language: English
• Subjects: 101/1; 13/106; 13/109; 13/95; 14/33; 38/35; 38/89; 42; 45; 631/67/1347; 631/80/84/2336; 631/80/84/2341; 64/60; 96; 96/10; Actin; Adenocarcinoma; Animals; Biology; Biomedical and Life Sciences; Biosensors; Breast cancer; Breast Neoplasms - pathology; Breast Neoplasms - secondary; Cdc42 protein; Cell Line, Tumor; Cyclin-dependent kinase inhibitor p21; Extracellular matrix; Female; Fluorescence resonance energy transfer; Guanosine triphosphatases; Humans; Invasiveness; Life Sciences; Mammary Neoplasms, Animal - pathology; Mammary Neoplasms, Animal - secondary; Matrix metalloproteinase; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Metalloproteinase; Metastases; Metastasis; Mice; Mice, SCID; Neoplasm Invasiveness - genetics; Neoplasm Metastasis - genetics; Rats; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02583-3

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. Hülsemann et al. examine the role of TC10, a p21 small GTPase, in breast cancer invasion and metastasis, by regulating membrane type-1 matrix metalloproteinase (MT1- MMP) at invadopodia. The authors also develop a FRET biosensor for TC10, which is used to further investigate p190RhoGAP-dependent regulation of spatiotemporal TC10 activity.