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等治疗方法表现出不同的反应 抑制剂或抗PD-1(APD1)免疫治疗。这种反应的异质性可能完全是由肿瘤引起的。 细胞固有的生物学差异或更有可能是肿瘤与器官部位特异性的共适应 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/或治疗研究 每个患者的反应限于一个肿瘤，大多数肿瘤来自更容易接近的部位，如 作为皮肤。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。该项目将衍生出这一点 通过综合分析不仅对不同器官部位的黑色素瘤损害，而且对其 来自温热尸检的相邻和非相邻的正常器官组织。 通过对邻近正常和非邻近肿瘤三联体的基因组和转录组分析 作为正常标本，这项研究开始剖析肿瘤及其宿主器官的共同进化。这个 初步分析已经揭示了几种可能与MAPK抑制剂有关的通路激活 (MAPKi)或免疫检查点阻断(ICB)抵抗脑、肝和脾转移。目标是 在一组更大的样本中，研究人员将评估肿瘤的异质性(在基因组、转录水平 和通路激活水平)，它们与转移生长和MAPKi/ICB反应模式的关系 每一个转移的器官。与此同时，研究小组将检查肿瘤附近正常组织的细胞 成分和途径激活。这些也将与器官特异性肿瘤的生长和 治疗耐药。PI在MAPKi和ICB抗性大基因组整合分析中的经验 肿瘤将是这项拟议工作成功的巨大财富。这项研究预计将发现和 验证迄今为止未知的黑色素瘤器官特异性转移决定因素和新机制(S) 对MAPKi和ICB的耐药性。

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.