Evaluating the TRa1-dependent characteristics of colon cancer stem cell biology
(2019) 9th French Meeting on Nuclear Receptors — Location: Lille, France (26.September.2019)
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- et. al.
- Abstract
- Background. Thyroid hormones (THs) control several aspects of gut development and homeostasis. They act through the thyroid hormone nuclear receptors TRs, that are T3-modulated transcription factors. The paradigm is the amphibian metamorphosis, where they are responsible for gut remodeling and emergence of the stem cells. In previous studies we showed that THs play a fundamental role in regulating the balance between cell proliferation and cell differentiation of the murine intestinal epithelial stem and progenitor cells. From a molecular point of view the nuclear receptor TRa1 controls several proliferation/cell-cycle genes as well as the Wnt and Notch pathways. In accordance with these functions, targeted expression of TRa1 in the intestinal epithelium (vil-TRα1 mice) is sufficient to induce aberrant and hyper-proliferative crypts and confers increased susceptibility to Apc-mutation dependent intestinal tumorigenic program (vil-TRα1/Apc+/1638N mice) (Kress et al, 2010). The translational potential of our studies in mouse models has been proved in human colorectal cancer (CRC) patients as we observed increased TR1 expression in CRC and, from a molecular point of view, we showed a significant correlation between TR1 levels and Wnt activity. TRα1 loss-of-function (LOF) and gain-of-function (GOF) in human adenocarcinoma Caco2 cell lines not only confirmed that TRa1 levels control Wnt activity but also demonstrated the role of TRa1 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. Aim. To link TR1 expression, T3 levels and cancer stem cell biology we settled up a 3D culture system of spheroids based on Caco2 cells with altered TR1 expression (TR1 GOF/LOF). Results. We have started our study by analyzing the sphere-forming efficiency (number and size) of Caco2 cells and the cancer stem cell phenotype associated in TRa1 GOF/LOF settings. The preliminary results indicate that TR1 up-regulation increases while TR1 KD decreases the number and the size of spheres, strongly acting on their growth capacity. In addition, the altered growth is linked to alteration of stem cell markers. Perspectives. Together with confirming the preliminary results, we are currently performing studies on the spheres to define: - Their response to chemotherapy depending on TRa1 expression levels, upon treatment with usual drugs employed for CRC patients (FOLFOX, FOLFIRI); - The capacity of tumor spread upon spheres xenografts in nude mice. In conclusion, our preliminary results indicate that T3 treatment or modulating TRa1 expression has an effect on colon cancer stem cells. Our work opens a new perspective in the study of TH/TR1-dependent signal on the physiopathology of the intestinal stem cells.
- Affiliations
Cancer Research Center of Lyon (CRCL)
Citations
Giolito, M. V., & et al. (2019). Evaluating the TRa1-dependent characteristics of colon cancer stem cell biology. 9th French Meeting on Nuclear Receptors, Lille, France. https://hdl.handle.net/2078.5/267778