Exploring the Non-Genetic Reprogramming of Colorectal Cancer and Tumor Microenvironment

Non-genetic reprogramming, including but not limited to metabolomic and epigenetic, play an equally significant role in cancer development compared to genetic mutations. In most scenarios, non-genetic alterations of tumor cells are associated with their tumor microenvironment, which is highly related to tumor progress and efficiency of the treatment. Nevertheless, how cancer cells adapt their microenvironment by metabolomic or epigenetic reprogramming remains largely unknown. This dissertation started with exploring two scenarios in colorectal cancer (CRC) studies: the metabolic reprogramming of CRC liver metastasis and the epigenetic remodeling of CRC patient-derived models of cancer. In the study of CRC liver metastasis (Chapter 2), we found that metastatic CRC cells promote their fructose metabolism in the liver by upregulating ALDOB. Knocking down ALDOB or restricting the dietary fructose can suppress CRC liver metastasis. In addition, we examined the potential therapeutic approach for liver metastasis with a KHK inhibitor. For the patient-derived models of cancer (PDMC) project (Chapter 3), we developed six matched PT-PDMC sets and performed ATAC-seq and mRNA to study the chromatin accessibilities of CRC cells. We found two-axis chromatin remodeling separating PDMC from the original patient sample (axis #1) as well as the different cancer models (axis #2). PDOX is more similar to PDX than organoids suggesting the chromatin remodeling of CRC cells is under the pressure of tumor microenvironment in PDMC. We also identified the two transcript factors, KLF14 and EGR2, which respond to the xenografts’ environment by footprinting analysis. These two TFs and their downstream gene, EPHA4, altered CRC tumor growth and drug sensitivities. Therefore, chromatin remodeling of different PDMC may interfere with their ability to predict therapeutic outcomes. In the last part of the dissertation (Chapter 4), I developed a novel system that can label and manipulate the tumor niche in situ. This method provides tools for studying the non-genetic alterations of CRC cells when they interact with the tumor microenvironment. Taken together, this dissertation presents a comprehensive understanding of the non-genetic reprogramming of colorectal cancer and its tumor microenvironment. It advances both the knowledge of non-genetic reprogramming in colorectal cancer and technologies to study the tumor microenvironment.