MT4-MMP (MMP17) as a therapeutic target in metastatic solid tumors

Others and we have identified the glycosylphosphatidyl inositol (GPI) anchored MMP called MT4-MMP or MMP-17 as a main driver of cancer cell metastasis in breast (1-3), head and neck (4) and colon cancers (5). More recently, we demonstrated a functional link between MT4-MMP and EGFR signaling in promoting breast cancer cell proliferation in vivo and in 3D culture models. We found that MT4-MMP is a key partner of EGFR activation and signaling (6), which is independent of its enzymatic activity. In triple negative breast cancer (TNBC) cells, MT4-MMP promotes primary tumor growth and lung metastases (1,2). 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 including lobular and ductal carcinoma in situ, invasive carcinoma, triple negative ductal carcinoma and normal tissue. 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 the triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. TNBC are known to express high level of EGFR and treatment options are limited due to the non-response of the TNBC patients to the EGFR targeted therapy. By investigating 86 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 at the cell surface. Altogether, we are providing mechanistic insights on how MT4-MMP availability is regulated and revealing unique features of this MT-MMP 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) Chabottaux et al., 2006, Cancer Res 66, 5165-5172;
(2) Host et al., 2012, Int. J. Cancer 131(7):1537-48;
(3) Rizki et al., 2008, Cancer Res 68, 1378-1387),
(4) Huang et al., 2009, Neoplasia 11, 1371-1382)
(5) Nimri et al., 2013, Mol Carcinog 52, 859-870
(6) Paye et al., 2014, Cancer Res. 74(23):6758-70