**8. Conclusion and future perspectives**

Our results indicate that RA signaling, when dysregulated, plays a major role in the SC origin of CRC. Overall, our review provides a strong rationale for future exploration of retinoid therapies for CRC in precision oncology. A few clues gleaned from our review are as follows: (i) drug screens using CRC cell lines (**Table 1**) and knockout of RA-signaling genes in human CRC cells might identify which retinoid drugs are active against cells with specific mutations; (ii) *Apc*Min/+ mice may be useful to identify additional retinoid agents that are active against *Apc* mutant tissues; (iii) strategies for designing retinoid-based CRC therapies will likely need to incorporate retinoids into drug combination regimens; (4) CRCs will likely need to be genotyped to determine the status of RA signaling genes when administering RA-based treatments to CRC patients. Finally, continued discovery of the mechanisms that explain how RA signaling regulate normal colon SCs and how dysregulation of RA signaling in cancer SCs drive CRC growth should provide insight into how new SC-targeted therapies might be designed for CRC.

## **8.1 Materials and methods**

The bioinformatics analysis on overexpression and mutation of RA signaling component genes in CRCs was done through the COSMIC website (cancer.sanger. ac.uk/cosmic). Bioinformatics analysis to identify RA signaling genes that predict CRC patient survival was done through The Human Protein Atlas (https://www. proteinatlas.org).
