IGF2BP3 is essential for the growth heterogeneity of colorectal adenoma cells by regulating MYC

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. On the other hand, the non-genetic mechanisms in the adenoma-carcinoma sequence remain largely unknown. In this study, organoids were established from 31 colorectal adenomas from 19 patients. Some adenomas showed heterogeneity in the proliferative potential of single cells, and this heterogeneity was regulated by non-genetic mechanisms. IGF2BP3 was identified as a differentially expressed gene between organoids with different growth patterns. 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. 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.