Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.
Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.
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DOI：
10.1158/2159-8290.cd-22-0427
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发表时间：
2023-01-09
期刊：
影响因子：
28.2
通讯作者：
White, Richard M.
中科院分区：
文献类型：
--
作者：
Suresh, Shruthy;Rabbie, Roy;Garg, Manik;Lumaquin, Dianne;Huang, Ting -Hsiang;Montal, Emily;Ma, Yilun;Cruz, Nelly M.;Tang, Xinran;Nsengimana, Jeremie;Newton-Bishop, Julia;Hunter, Miranda V.;Zhu, Yuxin;Chen, Kevin;de Stanchina, Elisa;Adams, David J.;White, Richard M.
人黑色素瘤转录特征的体内筛选鉴定了游离胆固醇在激活AP-1转移程序中的作用。在黑色素瘤中，预测哪些肿瘤最终会转移指导治疗决策。原发性肿瘤的转录特征已被用于预测转移，但其中哪些是驾驶员或乘客事件仍不清楚。我们使用来自辅助AVAST-M试验的数据来确定最终转移的局部肿瘤中的预测基因特征。使用原发性黑色素瘤的斑马鱼模型，我们在体内询问了来自AVAST-M签名的顶级基因。这一发现将胆固醇转移蛋白GRAMD 1B确定为真正的转移抑制因子，大多数敲除动物迅速发生转移。从机制上讲，过量的游离胆固醇或其代谢物27-羟基胆固醇通过激活AP-1程序促进侵袭性，这与人类转移增加有关。我们的数据表明，转移的转录种子嵌入在局部肿瘤中，这表明这些程序的早期靶向可用于预防转移复发。我们分析了人类黑色素瘤转录组学数据，以确定预测转移的基因特征。为了快速测试临床特征，我们在成年斑马鱼中建立了一个遗传转移平台，并将GRAMD 1B鉴定为黑色素瘤转移的抑制因子。GRAMD 1B相关胆固醇超载激活AP-1程序以促进黑色素瘤侵袭 这篇文章在本期专题中突出显示，第1页
An in vivo screen of a human melanoma transcriptional signature identified a role for free cholesterol in activating an AP-1 metastasis program. In melanoma, predicting which tumors will ultimately metastasize guides treatment decisions. Transcriptional signatures of primary tumors have been utilized to predict metastasis, but which among these are driver or passenger events remains unclear. We used data from the adjuvant AVAST-M trial to identify a predictive gene signature in localized tumors that ultimately metastasized. Using a zebrafish model of primary melanoma, we interrogated the top genes from the AVAST-M signature in vivo. This identified GRAMD1B, a cholesterol transfer protein, as a bona fide metastasis suppressor, with a majority of knockout animals rapidly developing metastasis. Mechanistically, excess free cholesterol or its metabolite 27-hydroxycholesterol promotes invasiveness via activation of an AP-1 program, which is associated with increased metastasis in humans. Our data demonstrate that the transcriptional seeds of metastasis are embedded within localized tumors, suggesting that early targeting of these programs can be used to prevent metastatic relapse. We analyzed human melanoma transcriptomics data to identify a gene signature predictive of metastasis. To rapidly test clinical signatures, we built a genetic metastasis platform in adult zebrafish and identified GRAMD1B as a suppressor of melanoma metastasis. GRAMD1B-associated cholesterol overload activates an AP-1 program to promote melanoma invasion. This article is highlighted in the In This Issue feature, p. 1