Metastatic Clonal Heterogeneity and its Impact on Melanoma Therapeutic Resistance

摘要 转移到不同器官的黑色素瘤通常对BRAF等疗法表现出异质性反应 抑制剂或抗PD-1（aPD-1）免疫疗法。这种反应的异质性可能是由于严格的肿瘤 细胞内在的生物学差异或更可能是肿瘤与器官部位特异性 微环境然而，大多数以患者为中心的转移性黑色素瘤生物学和/或治疗性黑色素瘤的研究， 反应限于每个患者一个肿瘤，肿瘤主要来自更容易接近的部位， 就像皮肤。因此，缺乏器官部位特异性适应的临床相关知识， 黑色素瘤转移及其对治疗反应的可能影响。这个项目将从这个 通过全面分析不仅对不同器官部位的黑色素瘤病变， 来自热尸检的相邻和非相邻正常器官组织。 通过对肿瘤三联体、相邻正常和非相邻肿瘤三联体的整合基因组学和转录组学分析， 正常标本，这项研究着手解剖肿瘤及其宿主器官的共同进化。的 初步分析已经揭示了几种可能与MAPK抑制剂相关的途径激活 在脑、肝和脾转移瘤中的MAPKi或免疫检查点阻断（ICB）抗性。目标是 更大的标本集，研究人员将评估肿瘤异质性（在基因组，转录组， 和途径活化水平），它们与转移性生长和MAPKi/ICB反应模式的相关性， 每个转移器官同时，研究小组将检查肿瘤邻近正常组织的细胞 组合物和途径激活。这些也将与器官特异性肿瘤生长相关， 治疗阻力PI在MAPKi和ICB抗性的大组学整合分析中的经验 肿瘤将是一个巨大的资产，为成功的拟议工作。这项研究有望发现和 证实迄今未知的黑色素瘤器官特异性转移的决定因素和新机制 对MAPKi和ICB的抗性。

ABSTRACT Melanomas metastasizing to different organs often display heterogenous responses to therapies such as BRAF inhibitor or anti-PD-1 (aPD-1) immunotherapy. This heterogeneity of responses may be due to strictly tumor cell-intrinsic biological differences or more likely co-adaptation of the tumors with organ site-specific microenvironments. However, most patient-centric studies of metastatic melanoma biology and/or therapeutic responses are limited to one tumor per patient, with a predominance of tumors from more accessible sites such as the skin. Thus, there is a dearth of clinically relevant knowledge of organ site-specific adaptations of melanoma metastases and their possible influence on therapeutic responses. This project will derive this knowledge through comprehensive analysis on not only melanoma lesions at distinct organ sites but also their adjacent and non-adjacent normal organ tissues from warm autopsies. Through integrative genomic and transcriptomic analysis of triplets of tumor, adjacent normal and non-adjacent normal specimens, this study sets out to dissect the co-evolution of the tumor and its host organs. The preliminary analyses have already revealed several pathway activations that may be related to MAPK inhibitor (MAPKi) or immune checkpoint blockade (ICB) resistance in the brain, liver and spleen metastases. Aiming for a larger set of specimens, the researchers will assess the tumor heterogeneity (at the genomic, transcriptomic and pathway activation levels), their association with metastatic growth and MAPKi/ICB response patterns in each metastatic organ. In parallel, the research team will examine the tumor-adjacent normal tissues' cellular composition and pathway activations. These will also be correlated with organ-specific tumor growth and treatment resistance. The PI's experiences in large omic integration analyses of MAPKi and ICB resistant tumors will be a tremendous asset for the success of the proposed work. This study is expected to discover and validate heretofore unknown determinants of organ-specific metastasis in melanoma and novel mechanism(s) of resistance to MAPKi and ICB.