Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling

Abstract

Colorectal cancer is the third most incidental cancer worldwide, and the response rate of current treatment for colorectal cancer is very low. Genome-scale metabolic models (GEMs) are systems biology platforms, and they had been used to assist researchers in understanding the metabolic alterations in different types of cancer. Here, we reconstructed a generic colorectal cancer GEM by merging 374 personalized GEMs from the Human Pathology Atlas and used it as a platform for systematic investigation of the difference between tumor and normal samples. The reconstructed model revealed the metabolic reprogramming in glutathione as well as the arginine and proline metabolism in response to tumor occurrence. In addition, six genes including ODC1, SMS, SRM, RRM2, SMOX, and SAT1 associated with arginine and proline metabolism were found to be key players in this metabolic alteration. We also investigated these genes in independent colorectal cancer patients and cell lines and found that many of these genes showed elevated level in colorectal cancer and exhibited adverse effect in patients. Therefore, these genes could be promising therapeutic targets for treatment of a specific colon cancer patient group.

Alteration of Proteotranscriptomic Landscape Reveals the Transcriptional Regulatory Circuits Controlling Key-Signaling Pathways and Metabolic Reprogramming During Tumor Evolution

“…Energy metabolism pathways including glucose metabolism and metabolic reprogramming were associated with correlation-enhancing genes, whereas respiratory electron transport chain and oxidative phosphorylation were linked to the correlation-repressing genes in the tumor tissues compared to non-tumor tissues in the rS-pS group (Figures 5A, 6A). The reprogramming of energy metabolism pathways in colon cancer has been previously reported by several studies (Satoh et al, 2017;Brown et al, 2018;Zhang et al, 2019). When we investigated the gene-centric correlation alterations between early and late stages of tumor tissues, surprisingly the genes associated with oxidative phosphorylation and electron transport chain were highly correlated in early stages, while their correlation decreased dramatically in late stages (Figure 7E), thereby underscoring a stage-dependent regulation of these pathways.…”

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

“…Within such a complicated metabolic system, it is very difficult to identify potential targets in CSCs. However, recent studies have attempted to identify such targets by systematically linking the metabolic profiles of tumors with genome-wide transcriptome and proteomics analysis [ 142 , 199 , 200 , 201 ]. In the near future, by accumulating such research data, it is expected that the identification of the metabolic vulnerabilities of each tumor will be possible, which will enable the development of more efficient diagnostic techniques and therapies.…”

Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

“…PPARα-sensitive genes during starvation include Cxcl10 and Rab30 (63). RRM2 plays oncogenic roles in tumorigenesis (50) and is a poor prognostic factor for colon, breast, and pancreatic cancers (51)(52)(53)(54).…”