Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow-Resident Melanoma CTCs.
Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow-Resident Melanoma CTCs.
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DOI：
10.1158/0008-5472.can-18-0644
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发表时间：
2018-09-15
期刊：
影响因子：
11.2
通讯作者：
Marchetti D
中科院分区：
文献类型：
--
作者：
Vishnoi M;Boral D;Liu H;Sprouse ML;Yin W;Goswami-Sewell D;Tetzlaff MT;Davies MA;Oliva ICG;Marchetti D
全身转移是黑色素瘤死亡的主要原因，黑色素瘤是最致命的皮肤癌形式。尽管大多数黑色素瘤患者在原发性和转移性肿瘤的发作之间表现出相当大的差距，但与转移潜伏期有关的信号传导机制仍不清楚。我们假设黑色素瘤循环肿瘤细胞（CTC）在疾病进展的无症状阶段归巢并驻留在骨髓（BM）中。使用耗尽正常细胞谱系（Lin-neg）的策略，我们从转移性黑色素瘤患者的血液中分离CTC富集的细胞群，通过推定CTC的存在来验证，所述推定CTC的特征在于黑色素瘤特异性生物标志物和参与细胞存活和促发育功能的上调基因转录物。在NSG小鼠（CTC衍生的异种移植物，即CDX）中植入Lin-neg群体，以及随后的离体骨髓驻留肿瘤细胞（BMRTC）与CTC的转录组学分析将蛋白泛素化鉴定为BMRTC信号传导的重要调控途径。选择性抑制USP7（一种关键的去泛素化酶），可阻止BM局部的BMRTC，并减少全身微转移。本研究首次提供证据表明，转移性黑色素瘤的无症状进展可以使用患者分离的CTC在体内重现。此外，这些结果表明，USP7抑制剂值得进一步研究，作为预防进展为明显临床转移的策略。
Systemic metastasis is the major cause of death from melanoma, the most lethal form of skin cancer. Although most melanoma patients exhibit a substantial gap between onset of primary and metastatic tumors, signaling mechanisms implicated in the period of metastatic latency remain unclear. We hypothesized that melanoma circulating tumor cells (CTCs) home to and reside in the bone marrow (BM) during the asymptomatic phase of disease progression. Using a strategy to deplete normal cell lineages (Lin-neg), we isolated CTC-enriched cell populations from blood of metastatic melanoma patients, verified by the presence of putative CTCs characterized by melanoma-specific biomarkers and upregulated gene transcripts involved in cell survival and pro-development functions. Implantation of Lin-neg population in NSG mice (CTC-derived xenografts, i.e. CDXs), and subsequent transcriptomic analysis of ex vivo bone marrow-resident tumor cells (BMRTC) vs. CTC identified protein ubiquitination as a significant regulatory pathway of BMRTC signaling. Selective inhibition of USP7, a key deubiquinating enzyme, arrested BMRTC in BM locales and decreased systemic micro-metastasis. This study provides first time evidence that the asymptomatic progression of metastatic melanoma can be recapitulated in vivo using patient-isolated CTC. Furthermore, these results suggest that USP7 inhibitors warrant further investigation as a strategy to prevent progression to overt clinical metastasis.