Teneurin-4 esercita un ruolo prometastatico nel cancro al seno triplo negativo

Teneurin-4 (TENM4), that belongs to the Teneurins family of transmembrane proteins, takes role in different physiological processes involving the nervous system, such as synaptic organization, synaptic partner matching, neuronal migration, and axonal guidance. Of note, TENM4 is involved in cell-cell and cell-extracellular matrix interactions, and its mutations and rearrangements have been found in several tumors. It has been demonstrated that TENM4 expression is up-regulated in Triple Negative Breast Cancer (TNBC) patients. TENM4 also has been indicated as a novel biomarker since it has been found higher levels in plasma of tumor bearing mice and TNBC patients compared to the healthy controls. However, the mechanisms underlying its role in cancer is still unknown. Meta-analysis of breast cancer datasets shows that TENM4 mRNA is up-regulated in invasive carcinoma specimens compared to healthy breast tissues and that the high expression of TENM4 correlates with shorter relapse-free and overall survival in TNBC - an aggressive subtype of breast cancer. In light of such information, it was aimed to clarify the link between TENM4 and TNBC and have a better understanding on the role of TENM4 in tumorigenesis. Both in vitro and in vivo strategies have been pursued exploiting murine TENM4 knock-out (KO) and wild-type (WT) TNBC cells. In vitro assays demonstrated a functional link between TENM4 expression and activation of Focal Adhesion Kinase (FAK) in controlling self-renewal and migration of TNBC cells and a higher invasive ability of TENM4-expressing over TENM4-deficient cells. No significant differences have been observed in tumor take and tumor growth rate upon the subcutaneous injection of TENM4-KO or TENM4-WT 4T1 cells in syngeneic mice; however, histopathological analyses on tumors suggest a possible involvement of TENM4 in inducing a pro-metastatic tumor microenvironment. Also, we found that TENM4 may play a role in matrix remodeling and tumor spreading. Accordingly, a striking reduction in lung metastases was revealed in TENM4-KO tumor-bearing mice compared to those bearing TENM4-expressing tumors. To detect the mechanisms underlying these results, we performed anoikis assays and looked for the presence of circulating tumor cells in the blood of tumor-bearing mice, finding that TENM4- KO and TENM4-WT 4T1 cells similarly stand anoikis, and a higher amount of CTC in the blood of TENM4-WT tumor-bearing mice compared to the TENM4-KO counterpart. Taken together, these findings suggest a prometastatic role of TENM4 and the potential to exploit TENM4 as a new biomarker and therapeutic target in TNBC.