Others and we identified the glycosylphosphatidyl inositol (GPI) anchored MMP called MT4-MMP or MMP-17 as a main driver of cancer cell metastasis in breast, head and neck and colon cancers. Recently, we demonstrated a functional link between MT4-MMP and EGFR signaling in promoting breast cancer cell proliferation. We found that MT4-MMP is a key partner of EGFR activation and signaling in triple negative breast cancer (TNBC) cells, which is independent of its enzymatic activity (1). Herein, we investigated the clinical relevance of our finding by immunohistochemical (IHC) study of MT4-MMP and EGFR expression in human samples of several breast cancer subtypes. IHC staining of normal breast tissues with MT4-MMP antibody show no signal, whereas breast carcinomas are positives for MT4-MMP. Of note, a strong staining for MT4-MMP was observed in TNBC samples. TNBC are known to express high level of EGFR and treatment options are limited due to the non-response of TNBC patients to EGFR targeted therapy. By investigating 88 TNBC tumors, we found a strong correlation between MT4-MMP and EGFR expression in a 68 % of TNBC tumors.
In parallel to the human study, by exploring the mechanism of MT4-MMP trafficking and internalization, we found for the first time that MT4-MMP can be recycled at the cell surface. Mechanistically, MT4-MMP uses a unique endocytic pathway, which relies on CLIC/GEEC route. In addition to deeply investigating its internalization dynamics, we also explored the mode of its oligomerization and dimerization in cancer cells. Altogether, we are providing mechanistic insights on how MT4-MMP availability is regulated and revealing its unique features among other MT-MMPs. These findings can be useful for designing therapeutics to block its presence at the cell surface, rather than merely blocking its enzymatic activity to block its pro-tumor effects.
(1) Paye et al., 2014, Cancer Res. 74(23):6758-70