Metastatic risk and resistance to BRAF inhibitors in melanoma defined by selective allelic loss of ATG5

Melanoma is a paradigm of aggressive tumors with a complex and heterogeneous genetic background. Still, melanoma cells frequently retain developmental traits that trace back to lineage specification programs. In particular, lysosome-associated vesicular trafficking is emerging as a melanoma-enriched lineage dependency. However, the contribution of other lysosomal functions such as autophagy to melanoma progression is unclear, particularly in the context of metastasis and resistance to targeted therapy. Here we mined a broad spectrum of cancers for a meta-analysis of mRNA expression, copy number variation and prognostic value of 13 core autophagy genes. This strategy identified heterozygous loss of ATG5 at chromosome band 6q21 as a distinctive feature of advanced melanomas. Importantly, partial ATG5 loss predicted poor overall patient survival in a manner not shared by other autophagy factors and not recapitulated in other tumor types. This prognostic relevance of ATG5 copy number was not evident for other 6q21 neighboring genes. Melanocyte-specific mouse models confirmed that heterozygous (but not homozygous) deletion of Atg5 enhanced melanoma metastasis and compromised the response to targeted therapy (exemplified by dabrafenib, a BRAF inhibitor in clinical use). Collectively, our results support ATG5 as a therapeutically relevant dose-dependent rheostat of melanoma progression. Moreover, these data have important translational implications in drug design, as partial blockade of autophagy genes may worsen (instead of counteracting) the malignant behavior of metastatic melanomas.黑色素瘤（Melanoma）是一类具有复杂异质性遗传背景的侵袭性肿瘤的典型范例。尽管黑色素瘤细胞的遗传背景复杂且异质性强，但其仍常保留可追溯至谱系特化程序的发育特征。其中，溶酶体相关囊泡运输正逐渐被证实为黑色素瘤富集的谱系依赖性特征。然而，自噬（autophagy）等其他溶酶体功能对黑色素瘤进展的贡献仍不明确，尤其在转移及靶向治疗耐药的背景下。本研究对多种癌症进行数据挖掘，针对13个核心自噬基因的mRNA表达水平、拷贝数变异及预后价值开展荟萃分析。该分析发现，位于染色体6q21条带的ATG5杂合缺失是晚期黑色素瘤的标志性特征。值得注意的是，ATG5的部分缺失可预测患者总生存期较差，这一特征并非其他自噬因子所共有，也无法在其他肿瘤类型中复现；且6q21区域的其他邻近基因并未体现出ATG5拷贝数的这种预后相关性。黑色素细胞特异性小鼠模型实验证实，Atg5的杂合（而非纯合）缺失可增强黑色素瘤的转移能力，并削弱靶向治疗的响应效果——以临床应用的BRAF抑制剂达拉非尼（dabrafenib）为例。综上，本研究结果表明ATG5可作为黑色素瘤进展的治疗相关剂量依赖性调控开关。此外，这些数据在药物研发中具有重要的转化意义：部分阻断自噬基因或许会加重（而非抑制）转移性黑色素瘤的恶性表型。