This Project received funding from the European Union’s Horizon 2020 research and innovation programme (Marie Skłodowska-Curie grant agreement No 839398)
FUNTRICAN
The adventure of this research project started in April 2019 and aim at discovering molecular mechanisms that direct the emergence and progression of colorectal cancer, along with the application of these findings for clinical treatment.
I am a Cancer Researcher based in Lyon, France. Since my PhD, my work is focused on understanding the early molecular alterations driving tumorigenesis. I am proud to be a Marie-Sklodowska Curie Fellow and I invite you to learn more about my work below.
ABOUT NICOLAS AZNAR
Nicolas Aznar is a young researcher in cancer biology at CNRS and a group leader at the Cancer Research Center of Lyon, CRCL (France). Dr. Aznar received his PhD degree in Molecular, Cellular Biology and Cancer from the University of Lyon. He completed his postdoctoral training in Cell Signaling and Cancer at the University of California San Diego, Department of Medicine and then at the CRCL, Department of Cancer Cell Plasticity. He studied a newly emerging subfamily of guanine nucleotide exchange modulators (GEMs) at UCSD where he identified GIV/Girdin as a novel effector of AMPK. He additionally defined an alternative pathway to modulate Wnt signals and discovered that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Daple protein. Lastly, he elucidated a long-standing question in the field of signal transduction on the molecular mechanisms by which interplay Wnt/Frizzled (FRZD), growth factor receptor-tyrosine kinases (RTKs) and heterotrimeric G-proteins, three major signaling hubs in eukaryotes. He joined the Cancer Research Center of Lyon in 2017 for his second postdoc when he secured a permanent research position in 2019. The major focus today of Nicolas’ group is studying the impact of the microenvironment (with a particular interest on thyroid hormones, cell metabolism and stress adaptation) on intestinal cell fate and determination with a relevance on therapy resistance in colorectal cancer.
OVERALL OBJECTIVES OF THE RESEARCH PROGRAM
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 (TRa and TRb) 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.
MAIN RESULTS ACHIEVED
Combining original approaches such as ex vivo 3D mouse and human organoid cultures, RNA seq analysis and innovative proteome mapping techniques, this project will 1) define the importance of the THs/TRs in CRC and their relative impact (individually or collectively) in CRC aggressiveness, and 2) help identifying novel interacting partners and highlight yet undescribed mechanisms of THs/TRs action, thus paving the way for new or better treatment alternatives for CRCs.
We recently demonstrated that inhibiting TRa1 in CRC patient tumors inhibits specifically 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.
A STEP INTO THE FUTURE
Combining original engineered cell lines, ex vivo 3D cultures, as well as powerful proteome mapping technique (BioID), this innovative project will enlarge the current studies of my group on TRa1 and TRb1 on colon cancer tumorigenesis and will surely contribute to define their functions in CRC aggressiveness. This project will therefore help in identifying novel markers for drug sensitivity that may contribute to establish "stratified therapy".
GET IN TOUCH
Cancer Research Center of Lyon (CRCL), France
UMR Inserm 1052, CNRS 5286
Centre Léon Bérard-Batiment Cheney D, 6ème étage
28 Rue Laennec 69373 Lyon Cedex 08
+33(0)469166680
+33(0)478782720
