Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression.
Antonin TortereauAntonin TortereauAmbroise ManceauAndrea ParadisiNicolas GadotJonathan VialDavid NevesLionel LarueMaxime BattistellaChristophe LeboeufCeleste LebbéAnne JaninPatrick MehlenPublished in: Cancer research (2019)
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.
Keyphrases
- cell death
- skin cancer
- mouse model
- squamous cell carcinoma
- papillary thyroid
- basal cell carcinoma
- type diabetes
- gene expression
- drug delivery
- genome wide
- endothelial cells
- signaling pathway
- young adults
- binding protein
- high resolution
- cancer therapy
- copy number
- induced apoptosis
- skeletal muscle
- mass spectrometry
- electronic health record
- big data
- squamous cell
- soft tissue