High-Fat Diet Driven Post-Operative Colon Cancer Recurrence is Dependent upon Genetic Susceptibility to Deoxycholic Acid [tRNA-seq]

The development of postoperative recurrent tumors or metastasis following surgical resection of colorectal cancer remains a major obstacle to colon cancer cure. While a high-fat diet is a risk factor for the development of recurrence, studies that examine the molecular mechanism by which diet drives postoperative tumors have been lacking. Here, using a murine model that mimics postoperative tumor formation, we show that the tumorigenic influence of a high-fat diet strongly depends on the genetic backbone of the primary tumor cells. We identify deoxycholic acid as a major contributor to the promotion of tumor recurrence only when the primary cancer cell line has an APC-driving, but not with an KRAS-driving mutation. We recapitulate the deoxycholic acid effect on the proliferation of tumoroids and identify the tumoroid response to the transcriptome expression and transfer RNA abundance, modification, and charging. The integrated analysis of mRNA and tRNA sequencing results reveals enhanced decoding of codons in proliferation-promoting genes. Our results provide a new understanding of how both diet and tumor genetics together lead to postoperative colorectal cancer recurrence. RNA-seq profiling of Organoid cells KPN (villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1icd/+) and AKPT (villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl TrgfbrIfl/fl) at 48 h after Deoxycholic Acid(DCA) treatment in comparison with untreated cells.