| First Author | Boussouar A | Year | 2020 |
| Journal | Cancer Res | Volume | 80 |
| Issue | 4 | Pages | 747-756 |
| PubMed ID | 31806640 | Mgi Jnum | J:285658 |
| Mgi Id | MGI:6392274 | Doi | 10.1158/0008-5472.CAN-18-1590 |
| Citation | Boussouar A, et al. (2020) Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression. Cancer Res 80(4):747-756 |
| abstractText | Deleted in colorectal cancer (DCC), the receptor for the multifunctional cue netrin-1, acts as a tumor suppressor in intestinal cancer and lung metastasis by triggering cancer cell death when netrin-1 is lowly expressed. Recent genomic data highlighted that DCC is the third most frequently mutated gene in melanoma; we therefore investigated whether DCC could act as a melanoma tumor suppressor. Reexpressing DCC in human melanoma cell lines promoted tumor cell death and tumor growth inhibition in xenograft mouse models. Genetic silencing of DCC prodeath activity in a BRAF(V600E) mouse model increased the proportion of mice with melanoma, further supporting that DCC is a melanoma tumor suppressor. Netrin-1 expression was elevated in melanoma compared with benign melanocytic lesions. Upregulation of netrin-1 in the skin cells of a BRAF(V600E)-mutated murine model reduced cancer cell death and promoted melanoma progression. Therapeutic antibody blockade of netrin-1 combined with dacarbazine increased overall survival in several mouse melanoma models. Together, these data support that interfering with netrin-1 could be a viable therapeutic approach in patients with netrin-1-expressing melanoma. SIGNIFICANCE: Netrin-1 and its receptor DCC regulate melanoma progression, suggesting therapeutic targeting of this signaling axis as a viable option for melanoma treatment. |
