Article Dans Une Revue Cancer Research Année : 2020

Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression

Ambroise Manceau
Andrea Paradisi
Nicolas Gadot
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Lionel Larue

Résumé

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.

Dates et versions

hal-02493700 , version 1 (25-01-2024)

Identifiants

Citer

Amina Boussouar, Antonin Tortereau, Ambroise Manceau, Andrea Paradisi, Nicolas Gadot, et al.. Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression. Cancer Research, 2020, 80 (4), pp.747-756. ⟨10.1158/0008-5472.CAN-18-1590⟩. ⟨hal-02493700⟩
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