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分子分析揭示了黑色素瘤脑转移的独特免疫和代谢特征。

Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases.

机构信息

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

出版信息

Cancer Discov. 2019 May;9(5):628-645. doi: 10.1158/2159-8290.CD-18-1489. Epub 2019 Feb 20.

DOI:10.1158/2159-8290.CD-18-1489
PMID:
30787016
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6497554/
Abstract

There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-C]-glucose tracing . IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance...

摘要

迫切需要提高我们对黑色素瘤脑转移（MBM）发病机制的理解。因此，我们对 88 例切除的 MBM 和 42 例患者匹配的颅外转移瘤进行了 RNA 测序；有足够组织的肿瘤还进行了全外显子组测序、T 细胞受体测序和免疫组化。MBM 表现出免疫浸润的异质性，与先前的放疗和开颅术后存活相关。与患者匹配的颅外转移瘤的比较表明，MBM 中存在显著的免疫抑制和氧化磷酸化（OXPHOS）富集。颅内和皮下异种移植的基因表达分析以及自发性 MBM 模型证实了 MBM 中 OXPHOS 基因表达增加，这也通过直接代谢物分析和 [U-C]-葡萄糖追踪检测到。IACS-010759 是一种目前处于早期临床研究阶段的 OXPHOS 抑制剂，改善了携带 MAPK 抑制剂耐药性颅内黑色素瘤异种移植的小鼠的存活，并抑制了自发性 MBM 模型中 MBM 的形成。该结果为 MBM 的发病机制和治疗耐药性提供了新的见解。意义：提高我们对 MBM 发病机制的理解将有助于合理开发和优先考虑新的治疗策略。本研究报告了迄今为止对患者匹配的 MBM 和颅外转移瘤最全面的分子分析。这些数据为 MBM 生物学和治疗耐药性提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/2708710edf89/nihms-1522084-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/1ea966736fd0/nihms-1522084-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/55352a5b987c/nihms-1522084-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/97b7a9e25e93/nihms-1522084-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/98b49510e665/nihms-1522084-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/28dea06e2ca2/nihms-1522084-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/2708710edf89/nihms-1522084-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/1ea966736fd0/nihms-1522084-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/55352a5b987c/nihms-1522084-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/97b7a9e25e93/nihms-1522084-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/98b49510e665/nihms-1522084-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/28dea06e2ca2/nihms-1522084-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1fde/6497554/2708710edf89/nihms-1522084-f0006.jpg

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