Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression
Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression
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DOI：
10.1158/0008-5472.can-18-1590
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发表时间：
2020-02-15
期刊：
影响因子：
11.2
通讯作者：
Mehlen, Patrick
中科院分区：
文献类型：
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作者：
Boussouar, Amina;Tortereau, Antonin;Mehlen, Patrick
在结直肠癌中缺失的是多功能信号通路netrin-1的受体，当netrin-1低表达时，它通过触发癌细胞死亡而在肠癌和肺转移中发挥肿瘤抑制作用。最近的基因组数据强调，DCC是黑色素瘤中第三个最常见的突变基因；因此，我们研究了DCC是否可以作为黑色素瘤的肿瘤抑制因子。在人黑色素瘤细胞系中重新表达DCC可促进移植瘤小鼠肿瘤细胞的死亡和肿瘤生长的抑制。在BRAF(V600E)小鼠模型中，DCC致死活性的遗传沉默增加了黑色素瘤小鼠的比例，进一步支持DCC是黑色素瘤的肿瘤抑制因子。与良性黑素细胞病变相比，Netrin-1在黑色素瘤中的表达升高。在BRAF(V600E)突变的小鼠模型中，Netrin-1的上调可以减少癌细胞死亡并促进黑色素瘤的进展。治疗性抗体阻断netrin-1联合达卡巴肼可增加几种小鼠黑色素瘤模型的总存活率。总之，这些数据支持干扰netrin-1可能是一种可行的治疗方法，用于治疗表达netrin-1的黑色素瘤患者。意义：netrin-1及其受体DCC调节黑色素瘤的进展，提示将该信号轴作为治疗黑色素瘤的可行选择。
Deleted in colorectal cancer (DCC), the receptor for the multi-functional 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 whetherDCCcould 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.