Examination of the Role of Membrane Type-1 Matrix Metalloproteinase (MTI-MMP) in Breast Cancer Metastasis

The membrane-tethered membrane type 1–matrix metalloproteinase (MT1-MMP) mediates proteolysis-based invasive tumor growth. In this issue, Marchesin et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201506002) describe a tug-of-war mechanism regulating dynein and kinesin motors to drive endosome tubulation and MT1-MMP delivery to the surface of cancer cells, identifying a crucial regulatory axis for tumor metastasis.

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

10.1101/2020.11.17.386854 ◽

2020 ◽

Author(s):

M. Hülsemann ◽

S.K. Donnelly ◽

P.V. Verkhusha ◽

S.P.H. Mao ◽

J.E. Segall ◽

...

Keyword(s):

Breast Cancer ◽

Extracellular Matrix ◽

Matrix Metalloproteinase ◽

Cancer Metastasis ◽

Small Gtpases ◽

Matrix Degradation ◽

Invasion And Metastasis ◽

Extracellular Matrix Degradation ◽

Membrane Type

AbstractDuring 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 demonstrated 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 invadopodia. By utilizing our new Förster resonance energy transfer (FRET) biosensor, we demonstrated the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates TC10 activity and function at invadopodia through the activation of p190RhoGAP and the downstream interacting effector Exo70 at the invadopodia sites. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10, on the invasive potential of breast cancer cells during invasion and metastasis.

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