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

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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.