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Novel cancer gene discovery using a forward genetic screen in RCAS-PDGFB-driven gliomas
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.ORCID iD: 0000-0002-0364-2709
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
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2023 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 25, no 1, p. 97-107Article in journal (Refereed) Published
Abstract [en]

Background Malignant gliomas, the most common malignant brain tumors in adults, represent a heterogeneous group of diseases with poor prognosis. Retroviruses can cause permanent genetic alterations that modify genes close to the viral integration site. Methods Here we describe the use of a high-throughput pipeline coupled to the commonly used tissue-specific retroviral RCAS-TVA mouse tumor model system. Utilizing next-generation sequencing, we show that retroviral integration sites can be reproducibly detected in malignant stem cell lines generated from RCAS-PDGFB-driven glioma biopsies. Results A large fraction of common integration sites contained genes that have been dysregulated or misexpressed in glioma. Others overlapped with loci identified in previous glioma-related forward genetic screens, but several novel putative cancer-causing genes were also found. Integrating retroviral tagging and clinical data, Ppfibp1 was highlighted as a frequently tagged novel glioma-causing gene. Retroviral integrations into the locus resulted in Ppfibp1 upregulation, and Ppfibp1-tagged cells generated tumors with shorter latency on orthotopic transplantation. In human gliomas, increased PPFIBP1 expression was significantly linked to poor prognosis and PDGF treatment resistance. Conclusions Altogether, the current study has demonstrated a novel approach to tagging glioma genes via forward genetics, validating previous results, and identifying PPFIBP1 as a putative oncogene in gliomagenesis.

Place, publisher, year, edition, pages
Oxford University Press, 2023. Vol. 25, no 1, p. 97-107
Keywords [en]
forward genetics screen, glioblastoma, liprin-beta-1, PDGFB, RCAS
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-496938DOI: 10.1093/neuonc/noac158ISI: 000834326400001PubMedID: 35738865OAI: oai:DiVA.org:uu-496938DiVA, id: diva2:1738685
Funder
EU, Horizon 2020, 640275Swedish Cancer SocietySwedish Research CouncilRagnar Söderbergs stiftelseSwedish Childhood Cancer FoundationAvailable from: 2023-02-22 Created: 2023-02-22 Last updated: 2023-02-22Bibliographically approved

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Weishaupt, HolgerČančer, MatkoRosén, GabrielaHolmberg, Karl O.Häggqvist, SusanaBunikis, IgnasJiang, YiwenSreedharan, SmithaGyllensten, UlfUhrbom, LeneAmeur, AdamSwartling, Fredrik J.

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Weishaupt, HolgerČančer, MatkoRosén, GabrielaHolmberg, Karl O.Häggqvist, SusanaBunikis, IgnasJiang, YiwenSreedharan, SmithaGyllensten, UlfBecher, Oren J.Uhrbom, LeneAmeur, AdamSwartling, Fredrik J.
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Science for Life Laboratory, SciLifeLabNeurooncology and neurodegenerationDepartment of Immunology, Genetics and PathologyGenomics and Neurobiology
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