Transcriptome and spatial analyses of tumor environment in addressing colorectal cancer racial and ethnical disparities

项目摘要 在美国，结直肠癌(CRC)是癌症相关死亡的第三大原因， 按种族和族裔划分的死亡率差异。差异在阿拉斯加原住民和 非洲裔美国人的死亡率是他们的2到3倍。这些差异是无法解释的 仅通过获得护理，表明其他促成因素，如分子亚型和细胞 异质性，需要揭开。不同种族和民族患者的肿瘤特征研究 将导致对CRC的新的生物学见解，这极大地克服了以前研究的局限性 主要只在非西班牙裔白人中进行。肿瘤免疫环境，指的是 肿瘤微环境内免疫渗入的空间组织和密度是复杂的 并与癌症预后相关。除了整体分析，尖端的空间单细胞分析使 US评估肿瘤组织不同区域(如边缘、中心)的肿瘤免疫环境， 将增加我们对免疫逃避和抗肿瘤免疫的知识，这对结直肠癌的生存至关重要。 我的目标是更好地了解推动肿瘤进展的分子和细胞景观 对种族和民族敏感的态度。这将为我提供新的实践中的多学科培训 综合肿瘤流行病学领域。我将利用一项嵌套病例对照研究的数据，该研究包括840 阿拉斯加原住民、非裔美国人、西班牙裔和非西班牙裔白人结直肠癌患者。每个种族和民族 包括70例死于结直肠癌的致命病例和140例存活时间至少与病例相同的结直肠癌对照病例 他们在年龄、性别和阶段上都是匹配的。在F99阶段，我将检查分子签名和 使用RNAseq数据制定四个种族和民族的预后指数。我要对肿瘤进行评估 使用空间分辨单细胞技术(Akoya)的阿拉斯加原住民患者的免疫环境 PhenoCycler)。在K00阶段，我将把转录和单细胞数据集成到患者级别的数据中，以 描述肿瘤的异质性及其在其他预后因素(如治疗、复发)中的作用。 该项目的结果将捕获完整的CRC转录和细胞生物学以及它们的 通过空间透镜与疾病结局的关系，并提供临床有用的预测工具 可为不同种族和民族的患者量身定做的预后。这将有助于解决长期存在的 儿童权利公约死亡率方面的种族和民族差异。这个项目为我提供了发展的培训机会 具有1)在不同种族和民族人群中从事分子流行病学工作的专长，特别是与 阿拉斯加原住民的参与，2)癌症免疫学，3)统计和计算分析 维度数据。这些经历将极大地帮助我过渡到博士后，并最终 在迅速发展的综合肿瘤流行病学领域中的独立癌症研究人员。

PROJECT ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related death in the US, with pronounced disparities in mortality by race and ethnicity. Disparities are particularly pronounced in Alaska Native and African American people with mortality rates being 2 to 3 times higher. These disparities cannot be explained by access to care alone, suggesting other contributing factors like molecular subtypes and cellular heterogeneity, need to be uncovered. Tumor profiling study in patients from multiple racial and ethnic groups will lead to novel biological insight into CRC, which greatly overcomes the limitation of previous studies that were conducted predominantly in non-Hispanic white people only. Tumor immune contexture, which refers to the spatial organization and density of the immune infiltrates within the tumor microenvironment, is complex and associated with cancer prognosis. Beyond bulk analysis, cutting-edge spatial single-cell analyses enable us to evaluate tumor immune contexture within different regions of tumor tissues (e.g. margin, center), which will add our knowledge of immune evasion and antitumor immunity that is critical for CRC survival. My objective is to better understand the molecular and cellular landscapes driving tumor progression in a racial- and ethnic-sensitive manner. This will provide me with hand-on, multi-disciplinary training in the new field of integrative tumor epidemiology. I will leverage data from a nested case-control study that includes 840 Alaska Native, African American, Hispanic and non-Hispanic White CRC patients. Each racial and ethnic group includes 70 lethal cases who died of CRC and 140 CRC controls who survived at least as long as the case to which they are matched for age, sex and stage. In the F99 phase, I will examine molecular signatures and develop a prognostic index across four racial and ethnic groups using RNAseq data. I will evaluate tumor immune contexture among Alaska Native patients using spatial-resolved single-cell technology (Akoya PhenoCycler). In the K00 phase, I will integrate transcriptomic and single-cell data into patient-level data to characterize tumor heterogeneity and its role in other prognostic factors (e.g. treatment, recurrence). Results from this project will capture a full spectrum of CRC transcriptional and cellular biology and their relationship to disease outcomes through a spatial lens and provide clinical-useful prediction tools for prognosis that can be tailored to racially- and ethnically-diverse patients. This will help to address longstanding racial and ethnic disparities in CRC mortality. This project provides me with training opportunities to develop expertise in 1) molecular epidemiologic working with racial and ethnic diverse populations, especially with the engagement of Alaska Native people, 2) cancer immunology, 3) statistical and computational analysis in high- dimensional data. Those experiences will greatly help my transition into a post-doctoral fellow and eventually an independent cancer researcher in the rapidly growing field of integrative tumor epidemiology.