Abstract:
: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 BRAFV600E 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 BRAFV600E-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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Boussouar A,Tortereau A,Manceau A,Paradisi A,Gadot N,Vial J,Neves D,Larue L,Battistella M,Leboeuf C,Lebbé C,Janin A,Mehlen Pdoi
10.1158/0008-5472.CAN-18-1590subject
Has Abstractpub_date
2020-02-15 00:00:00pages
747-756issue
4eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-18-1590journal_volume
80pub_type
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