دورية أكاديمية
Dual targeting of MAPK and PI3K pathways unlocks redifferentiation of Braf-mutated thyroid cancer organoids.
| العنوان: | Dual targeting of MAPK and PI3K pathways unlocks redifferentiation of Braf-mutated thyroid cancer organoids. |
|---|---|
| المؤلفون: | Lasolle H; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Schiavo A; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Tourneur A; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Gillotay P; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., de Faria da Fonseca B; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Ceolin L; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium.; Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Monestier O; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Aganahi B; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Chomette L; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Kizys MML; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Haenebalcke L; VIB, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium., Pieters T; VIB, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium.; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium., Goossens S; VIB, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium.; Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium., Haigh J; CancerCare Manitoba Research Institute, Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada., Detours V; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Maia ALS; Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre (HCPA), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil., Costagliola S; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium., Romitti M; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium. mirian.romitti@ulb.be. |
| المصدر: | Oncogene [Oncogene] 2024 Jan; Vol. 43 (3), pp. 155-170. Date of Electronic Publication: 2023 Nov 20. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2002->: Basingstoke : Nature Publishing Group Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987- |
| مواضيع طبية MeSH: | Proto-Oncogene Proteins B-raf* , Thyroid Neoplasms*/drug therapy , Thyroid Neoplasms*/genetics , Thyroid Neoplasms*/pathology, Animals ; Mice ; Carcinogenesis ; Mutation ; Organoids/pathology ; Phosphatidylinositol 3-Kinases/genetics ; Thyroid Cancer, Papillary/pathology |
| مستخلص: | Thyroid cancer is the most common endocrine malignancy and several genetic events have been described to promote the development of thyroid carcinogenesis. Besides the effects of specific mutations on thyroid cancer development, the molecular mechanisms controlling tumorigenesis, tumor behavior, and drug resistance are still largely unknown. Cancer organoids have been proposed as a powerful tool to study aspects related to tumor development and progression and appear promising to test individual responses to therapies. Here, using mESC-derived thyroid organoids, we developed a Braf V637E -inducible model able to recapitulate the features of papillary thyroid cancer in vitro. Overexpression of the murine Braf V637E mutation, equivalent to Braf V600E in humans, rapidly triggers to MAPK activation, cell dedifferentiation, and disruption of follicular organization. Braf V637E -expressing organoids show a transcriptomic signature for p53, focal adhesion, ECM-receptor interactions, EMT, and inflammatory signaling pathways. Finally, PTC-like thyroid organoids were used for drug screening assays. The combination of MAPK and PI3K inhibitors reversed Braf V637E oncogene-promoted cell dedifferentiation while restoring thyroid follicle organization and function in vitro. Our results demonstrate that pluripotent stem cells-derived thyroid cancer organoids can mimic tumor development and features while providing an efficient tool for testing novel targeted therapies. (© 2023. The Author(s).) |
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| معلومات مُعتمدة: | 825745 Fonds De La Recherche Scientifique - FNRS (Belgian National Fund for Scientific Research); PDR T.0140.14; CDR J.0068.22; PDR T.0230.18; Televie 7.4633.17/7.4526.19 Fonds De La Recherche Scientifique - FNRS (Belgian National Fund for Scientific Research) |
| المشرفين على المادة: | EC 2.7.1.- (Phosphatidylinositol 3-Kinases) EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) EC 2.7.11.1 (Braf protein, mouse) |
| تواريخ الأحداث: | Date Created: 20231121 Date Completed: 20240127 Latest Revision: 20240815 |
| رمز التحديث: | 20240815 |
| مُعرف محوري في PubMed: | PMC10786723 |
| DOI: | 10.1038/s41388-023-02889-y |
| PMID: | 37985676 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-5594 |
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| DOI: | 10.1038/s41388-023-02889-y |