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

dc.contributor.authorRenaud, Emilie
dc.contributor.authorRiegel, Christina
dc.contributor.authorRomero, Rossana
dc.contributor.authorSuryamohan, Kushal
dc.contributor.authorDistler, Ute
dc.contributor.authorTenzer, Stefan
dc.contributor.authorSchad, Arno
dc.contributor.authorMusholt, Thomas J.
dc.contributor.authorRajalingam, Krishnaraj
dc.date.accessioned2023-02-17T08:13:47Z
dc.date.available2023-02-17T08:13:47Z
dc.date.issued2022
dc.description.abstractBackground 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.sponsorshipGefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577de
dc.identifier.doihttp://doi.org/10.25358/openscience-8651
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/8667
dc.language.isoengde
dc.rightsCC-BY-4.0*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titleMultiomic analysis of papillary thyroid cancers identifies BAIAP2L1-BRAF fusion and requirement of TRIM25, PDE5A and PKCδ for tumorigenesisen_GB
dc.typeZeitschriftenaufsatzde
jgu.journal.titleMolecular cancerde
jgu.journal.volume21de
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.nameJohannes Gutenberg-Universität Mainz
jgu.organisation.number2700
jgu.organisation.placeMainz
jgu.organisation.rorhttps://ror.org/023b0x485
jgu.pages.alternative195de
jgu.publisher.doi10.1186/s12943-022-01665-yde
jgu.publisher.issn1476-4598de
jgu.publisher.nameBioMed Centralde
jgu.publisher.placeLondonde
jgu.publisher.year2022
jgu.rights.accessrightsopenAccess
jgu.subject.ddccode610de
jgu.subject.dfgLebenswissenschaftende
jgu.type.contenttypeScientific articlede
jgu.type.dinitypeArticleen_GB
jgu.type.resourceTextde
jgu.type.versionPublished versionde

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