SA1143: Evaluating the TRα1-dependent characteristics of colon cancer stem cell biology.
(2022) Digestive Disease Week — Location: San Diego, USA (21.May.2022)
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- et. al.
- Abstract
- Background. The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation (rev. in Skah et al, Dev. Biol_2017; Sirakov et al, CMLS_2014). The translational potential of our studies in mouse models has been proved in human colorectal cancer (CRC) patients as we observed increased TRα1 expression in CRC and, from a molecular point of view, we showed a significant correlation between TRα1 levels and Wnt activity (Uchuya-Castillo et al. 2018). TRα1 loss-of-function (LOF) and gain-of-function (GOF) in human adenocarcinoma Caco2 cell lines not only confirmed that TRα1 levels control Wnt activity but also demonstrated the role of TRα1 in regulating cell proliferation and migration. Altogether these data strongly suggested an involvement of TRa1 in cancer stem cell biology, similar to what we previously observed in normal intestinal stem cells (SC) (Godart et al, Dev. 2021). Aims. (1) define the basis of TRα1 upregulation in CRCs and (2) its impact in CSC biology. Methods. We analyzed the activity of THRA gene promoter (1) and used tumor spheroids based on Caco2 cells (Giolito et al, JoVE 2021) with altered TRα1 expression (2). Results. By THRA promoter analysis, we demonstrated the presence of binding sites for transcription factors involved in intestinal homeostasis and SC/CSC biology that are also altered in CRC, such as TCF7L2 (Wnt pathway), RBPJ (Notch pathway) and CDX2 (intestinal epithelial cell identity). In- depth analysis of the Wnt pathway allowed us to recapitulate the regulation of THRA transcription and TRα1 expression by this signaling pathway in human adenocarcinoma cell lines as well as mouse enteroids (Giolito et al, submitted). We studied the impact of altering TRα1 levels in tumor spheroids and observed that TRα1 up-regulation increases while TRα1 KD decreases the size of spheres, strongly acting on their growth capacity. Specific CSC populations are altered, as observed by IF and cytometry. We are in the process of evaluating the response to chemotherapy depending on T3/TRα1 by using drugs employed in CRC patients (FOLFOX, FOLFIRI). Conclusion and perspectives. Our work describes, for the first time, the regulation of the THRA gene in specific cell and tumor contexts. We also gained insights into the T3/TRα1-dependent tumor cell behavior, eventually including their response to chemotherapy. These studies are currently enlarged to mouse models and to human organoids.
- Affiliations
Université de Strasbourg, Inserm, IRFAC/UMR-S1113, FMTS. 3, Avenue Molière, 67200 Strasbourg, France
Citations
Giolito, M. V., & et al. (2022). SA1143: Evaluating the TRα1-dependent characteristics of colon cancer stem cell biology. Gastroenterology, 162(7), S321. https://doi.org/10.1016/S0016-5085(22)60770-4 (Original work published 2022)