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

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 Forster 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. Hulsemann 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.

Automated summary

The study reveals that TC10 GTPase regulates MT1-MMP at invadopodia during breast cancer metastasis, with its activity and function modulated by p190RhoGAP and Exo70.