FUNTRICAN · Functional analysis of thyroid hormone nuclear receptors TRs in human Intestinal Cancer stem cells
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-05-01 → 2021-04-30
- EU contribution
- €116,954
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
Lines connect the coordinator with its partners.
Results in brief
Functional analysis of thyroid hormone nuclear receptors TRs in human Intestinal Cancer stem cells
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.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union