Gutenberg Open Science: Multiomic analysis of papillary thyroid cancers identifies BAIAP2L1-BRAF fusion and requirement of TRIM25, PDE5A and PKCδ for tumorigenesis

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8651

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DC Field	Value	Language
dc.contributor.author	Renaud, Emilie	-
dc.contributor.author	Riegel, Christina	-
dc.contributor.author	Romero, Rossana	-
dc.contributor.author	Suryamohan, Kushal	-
dc.contributor.author	Distler, Ute	-
dc.contributor.author	Tenzer, Stefan	-
dc.contributor.author	Schad, Arno	-
dc.contributor.author	Musholt, Thomas J.	-
dc.contributor.author	Rajalingam, Krishnaraj	-
dc.date.accessioned	2023-02-17T08:13:47Z	-
dc.date.available	2023-02-17T08:13:47Z	-
dc.date.issued	2022	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8667	-
dc.description.abstract	Background Papillary thyroid carcinoma (PTC) is one of the most common forms of thyroid cancer with a cure rate of over 90% after surgery. However, aggressive forms may still occur, and personalized therapeutic strategies are increasingly required. Methods We performed integrated genomic and proteomic analysis of PTC tumor samples from patients who did not harbor BRAF or RAS mutations. We validate the analysis and present in-depth molecular analysis of the identified genetic rearrangement by employing biochemical and cell biological assays. Finally, we employ 3D spheroid models, loss of function studies and chemical inhibitors to target the hitherto upregulated factors. The data are analysed with appropriate statistical tests which are mentioned in the legends section. Results In a 23-year-old patient with thyroiditis, we identified a novel rearrangement leading to a BAIAP2L1-BRAF fusion that transforms immortalized human thyroid cells in a kinase and CC-domain dependent manner. Moreover, quantitative proteomic analysis of the same patient samples revealed the upregulation of several proteins including the Ubiquitin E3 ligase TRIM25, PDE5A, and PKCδ. Further, in a cohort of PTC patients, we observed higher expression of TRIM25 and PKCδ in the tumor and metastatic lesions, when compared to the matched normal tissue. Inhibition of TRIM25, PDE5A and PKCδ with small molecules or RNA interference affected not only viability and proliferation of BAIAP2L1-BRAF transformed cells, but also the viability, growth and invasion of corresponding 3D spheroid cultures. Conclusions Apart from unveiling a novel oncogenic BRAF fusion in PTCs, our data may open a novel avenue of therapeutic targeting in human PTCs.	en_GB
dc.description.sponsorship	Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	Multiomic analysis of papillary thyroid cancers identifies BAIAP2L1-BRAF fusion and requirement of TRIM25, PDE5A and PKCδ for tumorigenesis	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8651	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Molecular cancer	de
jgu.journal.volume	21	de
jgu.pages.alternative	195	de
jgu.publisher.year	2022	-
jgu.publisher.name	BioMed Central	de
jgu.publisher.place	London	de
jgu.publisher.issn	1476-4598	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	610	de
jgu.publisher.doi	10.1186/s12943-022-01665-y	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Lebenswissenschaften	de
Appears in collections:	DFG-491381577-G

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