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Endocrine Abstracts (2022) 84 OP01-06 | DOI: 10.1530/endoabs.84.OP-01-06

ETA2022 Oral Presentations Oral Session 1: Topic Highlights (6 abstracts)

Modeling braf-induced thyroid cancer development and cell redifferentiation using pluripotent stem cell-derived organoids

Hélène Lasolle 1 , Pierre Gillotay 2 , Lucieli Ceolin 3 , Benilda Aganahi 2 , Marina Malta Letro Kizys 4 , Ana Luiza Maia 5 , Sabine Costagliola 6 & Mirian Romitti 7


1Institut de Recherche Interdisciplinaire En Biologie Humaine et Moléculaire (Iribhm), Université Libre de Bruxelles (Ulb), Hospices Civils de Lyon, Université Lyon 1, Lyon, France; 2Institut de Recherche Interdisciplinaire En Biologie Humaine et Moléculaire (Iribhm), Université Libre de Bruxelles (Ulb), Brussels, Belgium; 3Ufrgs Universidade Federale Do Rio Grande Do Sul, Porto Alegre, Brazil; 4Escola Paulista de Medicina (Epm) and Institut de Recherche Interdisciplinaire En Biologie Humaine et Moléculaire (Iribhm), Medicine, Sao Paulo, Brazil; 5Hospital de Clínicas de Porto Alegre, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil; 6Université Libre de Bruxelles (Ulb); 7Universite Libre de Bruxelles, Institut de Recherche Interdisciplinaire En Biologie Humaine et Moléculaire (Iribhm), Université Libre de Bruxelles (U, Iribhm, Brussels, Belgium


Introduction: Due to their remarkable self-organizing structures and functional properties, organoid has become a powerful tool to model diseases ‘in a dish’. The use of organoids in cancer research emerged to better understand tumor behavior. Originally, adult stem cells (aSC)-derived organoids were derived from primary tumors while recent studies have reported the generation of cancer models arising from healthy cells by controlling oncogene expression. SC-derived cancer organoids can access the effects of oncogenes and early events driving tumorigenesis, role of cancer stem cells in tumor induction, genomic stability, effect of treatments and screening of new therapeutics.

Objectives: To generate a PTC organoid model by inducing the BrafV637E mutation in mouse ESC-derived functional thyroid follicles to better comprehend the oncogenic events driven by Braf-oncogene and develop a drug screening tool.

Methods: TRE-Nkx2-1-Pax8_bTg-NES-BrafV637E-ERT2 mESCs were differentiated into thyroid follicles with doxycycline and hrTSH/cAMP. After follicle enrichment BrafV637E activation was induced with 4-Hydroxytamoxifen (4OHT). Organoids were then treated with agents previously described to inhibit Braf oncogenesis (MEK, PI3K and histone deacetylase (VPA) inhibitors).

Results: TRE-Nkx2-1-Pax8_bTg-NES-Braf V637E-ERT2 mESCs were able to differentiate into functional thyroid follicles with iodinate-Tg (Tg-I) luminal accumulation. Starting six hours after 4OHT addition time-dependent dedifferentiation was observed; as evidenced by a decrease in mRNA expression of TSHR, Tg, Nis and Tpo. It was associated with an increase in ERK phosphorylation and proliferation. Activation of Braf V637E disrupted follicular organization and decreased Tg-I accumulation, 125I uptake and organification. Transcriptomic analysis revealed hyperactivation of PI3K-AKT-mTOR, TNF, cytokine signaling and promotion of Epithelial Mesenchymal Transition. Isolated inhibition of MEK and PI3K resulted in partial increase of Slc5a5/Nis levels, whereas treatment with VPA resulted in complete recovery. The combination of MEK and PI3K inhibitors resulted in complete re-expression of Nis, Tg, TSHR, Tpo and reorganization into functional follicles confirmed by the detection of Tg-I.

Conclusions: We demonstrate the generation of an mESC-derived organoid model that recapitulates the transcriptomic and 3D-histological features of PTC. The combination of MEK and PI3K inhibitors promoted Nis reexpression and thyrocyte redifferentiation with recovery of follicular functionality. This mESC-derived PTC in vitro model opens new opportunities to study early mechanisms of carcinogenesis while providing a simple and efficient tool for screening new treatments for thyroid cancer.

Volume 84

44th Annual Meeting of the European Thyroid Association (ETA) 2022

Brussels, Belgium
10 Sep 2022 - 13 Sep 2022

European Thyroid Association 

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