IGF2BP3 plays a critical role in the growth heterogeneity of colorectal adenoma cells by regulating MYC expression [mouse RNA-seq]
Background & Aims: Colorectal adenoma is a major precancerous lesion in colorectal cancer (CRC), and the adenoma-carcinoma sequence is a well-known multistep progression to CRC caused by the accumulation of genetic mutations. Accumulating evidence suggests that intra-tumor heterogeneity in CRC is influenced not only by genetic alterations, but also by non-genetic mechanisms. However, in adenomas, the non-genetic mechanisms remain largely unknown. Methods: Organoids were isolated from colorectal adenoma tissue. Single cells derived from patient-derived adenoma organoids were evaluated for their proliferative potential. The growth patterns of single-cell-derived spheroids were divided into two groups (D-/S-pattern) and the molecular mechanisms underlying the differences in growth patterns were examined. Results: Organoids were established from 31 colorectal adenomas from 19 patients. Some adenomas showed heterogeneity in the proliferative potential of single cells, as observed in CRC, and this heterogeneity was regulated by non-genetic mechanisms. IGF2BP3 was identified as a differentially expressed gene between organoids with different growth patterns and was found to be a key regulator of the high proliferative potential of adenomas. IGF2BP3 positively regulated MYC expression at the transcriptional level and negatively regulated it at the translational level. This promoted high proliferative potential with high levels of oxidative phosphorylation, while allowing cells to avoid MYC-induced cell death. IGF2BP3 affected the tumorigenicity of mouse adenomas in vivo. Conclusion: Intra-tumor heterogeneity in growth potential is acquired at the precancerous stage in the adenoma-carcinoma sequence of colorectal carcinogenesis, and IGF2BP3 plays an important role in regulating MYC levels. These findings provide new insights into the non-genetic regulation of adenomas during CRC development. Overall design: RNA-seq profiling of intestinal organoids derived from Apc-knockout mice with and without IGF2BP3 overexpression