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Functional analysis of thyroid hormone nuclear receptors TRs in human Intestinal Cancer stem cells

Periodic Reporting for period 1 - FUNTRICAN (Functional analysis of thyroid hormone nuclear receptors TRs in human Intestinal Cancer stem cells)

Reporting period: 2019-05-01 to 2021-04-30

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women worldwide. Although some colorectal cancers 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. Besides the deadly affliction that cancer is at individual level, there is an urgent need to find new or better treatment alternatives for colorectal cancers. Indeed, the cost of treatments was estimated in 2013 at 13,1 billion euros, representing 10% of the European health-care cost. In support of the well-documented contribution of cell microenvironment on tumorigenesis and resistance to conventional therapies, Thyroid hormones (THs) appear to promote tumor growth, metastasis, and survival in animal models, and may additionally influence the outcome of tumor therapy contributing to tumor relapse in patients. Despite controversial data supporting that either hypo- or hyper-thyroidism promotes CRC development, identify mechanisms of action of THs/TRs (TRa1 and TRb1) axis is a prerequisite to open novel therapeutic avenues.

The objectives of this Marie Sklodowska Curie Action (MSCA) were to unravel (1) how CRC tumors behave in their hormonal microenvironment by enlarging the current understanding on the molecular mechanism of TRs’ functions in CRC aggressiveness and (2) to evaluate the therapeutic potential of targeting TRa1 and TRb1 activity for designing novel therapies to treat CRC. By developing FUNTRICAN project, our findings further explored the oncogenic role of THs and TRs in CRC where we identified an antagonist role of TRa1 and TRb1 in CRC tumorigenesis and more importantly confirmed that modulating TRa1 and TRb1 activity impact CRC sensibility to conventional therapies opening thereby a new avenue to prevent tumour relapse.
The MSCA fellow obtained a permanent researcher position at the French National Centre for Scientific Research (CNRS) in a prestigious institute in Lyon during the MSCA fellowship, reflecting the positive impact of the MSCA individual fellowship on early career scientists.
The FUNTRICAN project was organized in 6 work packages (WP) combining original approaches such as ex vivo 3D spheroid assays, innovative 3D culture system development for mouse and human organoid cultures, RNA seq analysis and cutting-edge proteome mapping techniques. WP1, WP2 and WP3 led to the identification of TRa1 as a positive regulator of tumor growth and stem cell marker expression while TRb1 dampens it. More importantly, WP3 demonstrate that TRa1 inhibition in CRC patient tumors decreases cancer stem cells/Tumor initiating cells proliferation while TRb1 targets preferentially more differentiated cancer cells. Last but not least, this project established a proof of concept that targeting THs/TRs in combination with conventional chemotherapy improve the efficiency of the latter paving the way for new or better treatment alternatives for CRCs.

The management of the project was conducted under WP4. In WP5, for career development and training, the MSCA fellow supervised 3 master students and 1 postdoc, served as a peer reviewer for academic journals in his field and secured 150,000€ in funding from the CNRS “prematuration program” to conduct (as a PI) the technologic development of an innovative 3D organoid culture system crucial for the development of WP3 focused on CRC patient-derived organoids study and biobanking. Last but not least he obtained a permanent research position at the French National Centre for Scientific Research (CNRS). In WP6, the fellow delivered 1 international conference presentation, 1 published article in peer review journals (where FUNTRICAN was mentioned), 1 pending patent (#FR2013109), 1 video, 1 science fair organization and 2 seminars for charity events.

Results of this MSCA are reported in a forthcoming paper related to the technology development. The data collected during this MSCA will also feed at least two additional research publications in the next two years.
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.
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