The neuroepithelial origin of ovarian carcinomas explained through an epithelial-mesenchymal-ectodermal transition enhanced by cisplatin.

Autor:	Díaz-Carballo D; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany. david.diaz-carballo@marienhospital-herne.de., Safoor A; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Saka S; Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, USA., Noa-Bolaño A; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., D'Souza F; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Klein J; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Acikelli AH; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Malak S; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Rahner U; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Turki AT; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Höppner A; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Kamitz A; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany., Song W; The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China., Chen YG; The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China., Kamada L; Clinic of Pediatric Oncology, Hematology and Immunology, Düsseldorf University Hospital , 40225, Düsseldorf, Germany., Tannapfel A; Institute of Pathology, Ruhr University Bochum, Medical School, Bürkle-de-La-Camp-Platz 1, 44789, Bochum, Germany., Brinkmann S; Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Medical School, Bürkle-de-La-Camp-Platz 1, 44789, Bochum, Germany., Ochsenfarth C; Department of Anesthesia, Intensive Care, Pain and Palliative Medicine, Ruhr-University Bochum Medical School, Marien Hospital Herne, 44625, Herne, Germany., Strumberg D; Institute of Molecular Oncology and Experimental Therapeutics, Division of Hematology and Oncology, Ruhr University Bochum Medical School, Marien Hospital Herne, Düngelstr. 33, 44623, Herne, Germany.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2024 Nov 26; Vol. 14 (1), pp. 29286. Date of Electronic Publication: 2024 Nov 26.
DOI:	10.1038/s41598-024-76984-9
Abstrakt:	Acquired resistance to platinum-derived cytostatics poses major challenges in ovarian carcinoma therapy. In this work, we show a shift in the epithelial-mesenchymal transition (EMT) process towards an "ectodermal" conversion of ovarian carcinoma cells in response to cisplatin treatment, a progression we have termed epithelial-mesenchymal-ectodermal transition (EMET). EMET appears to occur via the classical EMT as judged by a) the downregulation of several epithelial markers and b) upregulation of Vimentin, accompanied by various embryonal transcription factors and, importantly, a plethora of neuronal markers, consistent with ectodermal differentiation. Moreover, we isolated cells from ovarian carcinoma cultures exhibiting a dual neural/stemness signature and multidrug resistance (MDR) phenotype. We also found that the epithelial cells differentiate from these neural/stem populations, indicating that the cell of origin in this tumor must in fact be a neural cell type with stemness features. Notably, some transcription factors like PAX6 and PAX9 were not localized in the nucleoplasm of these cells, hinting at altered nuclear permeability. In addition, the neuronal morphology was rapidly established when commercially available and primary ovarian carcinoma cells were cultured in the form of organoids. Importantly, we also identified a cell type in regular ovarian tissues, which possess similar neural/stemness features as observed in 2D or 3D cultures. The signature of this cell type is amplified in ovarian carcinoma tumors, suggesting a neuroepithelial origin of this tumor type. In conclusion, we propose that ovarian carcinomas harbor a small population of cells with an intrinsic neuronal/stemness/MDR phenotype, serving as the cradle from which ovarian carcinoma evolves. Competing Interests: Declarations. Competing interests: The authors declare no competing interests. (© 2024. The Author(s).)
Databáze:	MEDLINE
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