Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women worldwide. Although some CRCs are effectively treated through the standard strategy of surgery, radiation and/or chemotherapy, some patients have a recurrence of their cancer and a spread to other parts of the body that threatens life. Despite decades of research, we are unable to predict which cancers will be effectively treated and which are likely to spread. In support of the well-documented resistance of cancer stem cells (CSCs) to conventional therapies high stem cell (SC) signature scores statistically associate with a high risk of tumor relapse in patients. Targeting CSCs thus constitute a determinant medical issue and identify novel players of SC plasticity is a prerequisite to open novel therapeutic avenues. Using ex vivo organoid cultures, we recently demonstrated that thyroid hormones (THs) reduce the pool of intestinal SCs by triggering premature cell differentiation. Even if the underlying mechanisms remain elusive, our preliminary results tend to demonstrate that the TH-induced loss of stemness relies on a profound modification of the ratio between TRα1 and TRβ1 (TRs), with deep consequences on the expression of WNT and NOTCH downstream target genes. My proposal will pave the way for a unique focal area in the field of CSCs. Combining original approaches such as ex vivo 3D human colosphere and organoid cultures, in vivo CSC tracing experiments as well as innovative proteome mapping techniques (BioID and APEX2) I aim to address the potential interest of disrupting the THs/TRs balance in order to enforce CSC differentiation with the final aim to eradicate them by conventional therapies. Furthermore and more importantly, by minoring CSC plasticity, it will strongly reduce their adaptability to stress conditions and limit escape mechanisms.