This proposal focuses on colorectal cancer, but the results are likely to impact cancer research in general since THs/TRs dysregulation has been also involved in other types of cancers. This opens a new perspective in defining the function of THs and their nuclear receptors in gut development, stem cell biology and tumorigenesis. In one hand, our new data show that TRa1, found frequently overexpressed in colorectal tumors promotes SC and CSC proliferation. In the other hand, our experiments also show that TRb1 behave as a TRa1 antagonist in SCs in that a shift from TRa1 to TRb1 activation commits SC impoverishment. This, couple with the fact that TRb1 expression level has been shown to be down-regulated in several cancers, FUNTRICAN has shown today the potential interest of modulating TRs’ activity in order to enforce CSC differentiation with the final aim to eradicate them by conventional therapies.
Impact from the MSCA on the career development of the fellow are beyond expectation as he obtained a permanent research position in a famous french research institute. Before obtaining the MSCA fellowship, he wished to establish his own research program centered on the study of CSCs plasticity; more specifically, discovering and characterizing novel targets within the pathways that enhance the ability of CSCs to continue to self-renew, maintain pluripotency and thereby enable tumor relapse. Indeed, his research group is now actively analyzing the importance of complex interactions between signaling pathways in the intestinal stem cells.
With an overall failure rate in drug development of over 96%, including a 90% failure rate during clinical development there is an urgent need to establish more effective and stable preclinical tumor drug screening models to faithfully recapitulate the morphological and molecular characteristics of various human tumors. Tumor organoids could help in that way since they retained the genetic information of tumor tissue during long-term passages. However, since clonal drift inevitably occurred within these cultures, we need to improve culture standardization to guarantee (1) the success rate of tumor drug screening in clinical trials but also (2) the benefit for finding the most effective treatment for cancer patients. Therefore, the technology developed in FUNTRICAN project will facilitate studies on CRC tumor organoid cultures, but the methodology used is likely to impact also knowledge on tumoroid culture from other organs.
During the MSCA fellowship, he developed competences with many different research technics related to the organoid cell culture technology and manage to improve it drastically. From there, he developed an innovating 3D organoid culture system (patent pending #FR2013109) making him very competitive in the field and allowing him to develop a strong and interesting network of international scientists and industrial partners but also improved his communicating skills by sharing the results from the FUNTRICAN research program to a broad public.
