Function of the thyroid hormone nuclear receptor TRα1 in intestinal stem cell physiopathology
Function of the thyroid hormone nuclear receptor TRα1 in intestinal stem cell physiopathology
SUBGROUP LEADER
Our group is studying the mechanisms that regulate gut stem cell (SC) homeostasis in physiological and pathological conditions. Gut SCs physiology depends on a complex interplay between the various cell types that constitute the stem cell niche and that interact via complementary signalling pathways including Wnt, Notch and BMP. A set of recent evidences has unquestionably demonstrated that the alteration of this crosstalk contributes to the neoplastic transformation of the intestinal SC and promotes tumor initiation.
Within this context, we are actively studying the cellular and molecular processes of gut SC transformation with the aim to develop novel therapeutic strategies.
Current projects
Colorectal cancer (CRC) is one of the most common cancers in the world and the current therapeutic strategy includes surgical ablation and chemotherapy. However, the cancer reappears in 30-50% of cases. The peculiarity of the intestinal epithelium is its continuous renewal fuelled by multipotent stem cells (SC) located in the crypts, generating all differentiated cell types. Recent studies have highlighted that the crypt SC are the cells responsible for CRC. It is, in fact, proposed that their neoplastic transformation may be the cause of cancer stem cells (CSCs), known to support tumour growth, metastatic spread and responsible for drug resistance. In agreement with this hypothesis, a molecular signature of SCs is predictive of a high risk of recurrence in patients. Understand the mechanisms that control SC homeostasis and determine how their impairment contributes to the neoplastic transformation of these cells is needed to develop efficient diagnostic and therapeutic tools.
In this context, we are developing several complementary research axes. Indeed, our team showed the involvement of thyroid hormones through the TRa1 nuclear receptor in regulating the homeostasis of the intestinal epithelium precursor cells in physiological and pathological conditions. These results opened new perspectives in the study of this extrinsic signal in the physiopathology of the crypt SCs. In another research axis, we defined the activity of TRa1 in CRC biology and metastatic dissemination.
The aim of our current research activities is to better understand the regulatory networks governing the homeostasis of SCs and their contribution to neoplastic transformation as well as CRC progression. The project also takes into account functional interactions between the intrinsic factors of intestinal pathophysiology and external signals such as hormones and chemokines.
Main publications 2018-
Yao S, Bogutac P, Giolito MV, Pontoni L, Sirakov M, Plateroti M, Fabbricino M. Nano-sized natural organic matter interacts with bisphenol A and decreases cytotoxicity to human cells. Environmental Chemistry Letters 2024, accepted 6-02-2024.
Säisä-Borreill S, Davidson G, Kleiber T, Thevenot A, Martin E, Mondot S, Blottière H, Helleux A, Mengus G, Plateroti M, Duluc I, Davidson I and Freund JN (2023) General transcription factor TAF4 antagonizes epigenetic silencing by Polycomb to maintain intestine stem cell functions. Cell Death and Differentiation 30(3):839-853.
Giolito MV, La Rosa T, Farhat D, Bodoirat S, Guardia G, Domon-Dell C, Galante P, Freund JN and Plateroti M (2022) Regulation of the THRA gene, encoding the thyroid hormone nuclear receptor TRa1, in intestinal lesions. Molecular Oncology 16(22):3975-3993.
Giolito MV and Plateroti M (2022) Thyroid hormone signaling in the intestinal stem cells and their niche. Cellular and Molecular Life Sciences, 79(9):476. Invited review article.
Perra A and Plateroti M (2022) Targeting Thyroid Hormone-Dependent Pathways in Proliferative and Degenerative Disorders. Front. Med., 08 June 2022, doi.org/10.3389/fmed.2022.944769. Editorial Special Issue.
Sirakov M and Plateroti M (2022) Thyroid Hormone Signaling and Function: News from Classical and Emerging Models. Cells. 2022 Jan 28;11(3):453. Editorial Special Issue.
Sirakov M, Claret L and Plateroti M (2021). Thyroid Hormone Nuclear Receptor TRα1 and canonical WNT cross-regulation in normal intestine and cancer. Frontiers in Endocrinology, Special issue "Nuclear Receptors", 12:725708. Invited review.
Baroni M, Yi C, Choudhary S, Lei X, Kosti A, Grieshober D, Velasco M, Qiao M, Burns S, Araujo P, DeLambre T, Young M, Plateroti M, Marco Ferreira, Hasty P and Penalva L (2021) Musashi1 contribution to glioblastoma development via regulation of a network of DNA replication, cell cycle and division genes. Cancers 13(7):1494.
Godart M, Frau C, Farhat D, Giolito MV, Jamard C, Le Nevé C, Freund JN, Penalva LO, Sirakov M and Plateroti M (2021) The murine intestinal stem cells are highly sensitive to the modulation of the T3/TRa1-dependent pathway. Development 148(8):dev194357.
Frau C, Jamard C, Gaspard G, Guardia G, Machon C, Pilati C, Le Nevé C, Laurent-Puig P, Guitton J, Galante P, Penalva L, Freund J-N, De La Fouchardiere C and Plateroti M (2021) Deciphering the role of intestinal stem cell populations in resistance to chemotherapy. Cancer Research 81(10):2730-2744.
Giolito MV, Claret L, Frau C and Plateroti M (2021) A Three-dimensional Model of Spheroids to Study Colon Cancer Stem Cells. JoVE (Journal of Visualized Experiments), 167, e61783.
Plantamura E, Dzutsev A, Chamaillard M, Djebali S, Moudombi L, Boucinha L, Grau M, Macari C, Bauché D, Dumitrescu O, Rasigade JP, Lippens S, Plateroti M, Kress E, Cesaro A, Bondu C, Rothermel U, Heikenwälder M, Lina G, Bentaher-Belaaouaj A, Marie JC, Caux C, Trinchieri G, Marvel J, Michallet MC (2018) MAVS deficiency induces gut dysbiotic microbiota conferring a pro-allergic phenotype. Proc Natl Acad Sci U S A 115(41):10404-10409.
Uchuya-Castillo J, Aznar N, Frau C, Martinez P, Le Nevé C, Marisa L, Penalva L, Laurent-Puig P, Puisieux A, Scoazec JY, Samarut J, Ansieau S and Plateroti M (2018) Increased expression of the thyroid hormone nuclear receptor TRa1 characterizes intestinal tumors with high Wnt activity. Oncotarget 9: 30979-30996.
Sirakov M, Plateroti M (2018) In Vitro Approaches to Identify Thyroid Hormone Receptor-Dependent Transcriptional Response. Methods in Molecular Biology (Clifton, N.J.) Volume: 1801: 29-38.
Samarut J, Plateroti M (2018) Thyroid Hormone Receptors: Several Players for One Hormone and Multiple Functions. Methods in Molecular Biology (Clifton, N.J.) Volume: 1801: 1-8. Editorial.
Ducheix S, Peres C, Hardfeldht J, Frau C, Mocciaro G, Piccinin E, Lobaccaro JM, Plateroti M, Griffin JL, Ntambi J, Moschetta A (2018) Ablation of Stearoyl-CoA Deasaturase 1 in enterocytes drives intestinal inflammation and tumorigenesis that are rescued by dietary oleate. Gastroenterology, 155(5), 1524-1538.
Markossian, S., Guyot, R., Richard S., Teixeira, M., Aguilera, N., Bouchet, M., Plateroti, M., Guan, W., Gauthier, K., Aubert, D., Flamant, F. (2018) CRISPR/Cas9 editing of the mouse Thra gene produces models with variable resistance to thyroid hormone. Thyroid 28(1):139-150.