Integrative Metabolome and Transcriptome Analyses Provide Insights into PHGDH in Colon Cancer Organoids.

As a rate-limiting enzyme in endogenous serine de novo synthesis pathway, PHGDH has been widely concerned about its role in a variety of tumors including colon cancer and the development of inhibitors. In our previous study, we studied PHGDH in colon cancer cell lines. However, with the development of personalized therapy, we realized that in scientific research, 2D cell lines lost a lot of original characteristic information during long-term culture, and the results obtained may not be enough to support the conclusion.  Patient-derived tumor organoids maintain genomic stability and make up for information missing from cell lines due to monoclonal growth. Therefore, in our study, a colon cancer organoid with high PHGDH expression was selected, and was analyzed for transcriptomic and metabolomic changes through targeted inhibition of PHGDH. The results showed that inhibition of PHGDH significantly inhibited the proliferation of colon cancer organoids. The transcriptome, metabolome and combined omics analysis showed that the changes of colon cancer organoids after inhibition of PHGDH were mainly involved in PRSS1 and PRSS56, steroid hormone biosynthesis, phenylalanine metabolism, ascorbate and aldarate metabolism and tyrosine metabolism. In our study, the role of PHGDH in serine metabolism in colon cancer organoids was clarified by multi-omics analysis to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer.