RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis
| Autor: | Dionysia Dimitrakopoulou, Liza Eeckhout, Kris Vleminckx, Christian Vanhove, Rivka Noelanders, Jo Van Dorpe, Gert Van Isterdael, Dieter Tulkens, Suzan Demuynck, Marjolein Carron, Dieter Deforce, Thomas Naert, David Creytens |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Xenopus Retinoblastoma-Like Protein p107 Biology Xenopus Proteins medicine.disease_cause Retinoblastoma-like protein 1 Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine Glioma Pancreatic cancer Genetics medicine Animals Humans Carcinoma Small Cell neoplasms Molecular Biology Gene Editing Retinoblastoma Retinoblastoma protein medicine.disease Choroid plexus papilloma eye diseases Carcinoma Neuroendocrine Pancreatic Neoplasms Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Choroid plexus CRISPR-Cas Systems Carcinogenesis Glioblastoma Signal Transduction |
| Zdroj: | Oncogene. 39(13) |
| ISSN: | 1476-5594 |
| Popis: | Alterations of the retinoblastoma and/or the p53 signaling network are associated with specific cancers such as high-grade astrocytoma/glioblastoma, small-cell lung cancer (SCLC), choroid plexus tumors, and small-cell pancreatic neuroendocrine carcinoma (SC-PaNEC). However, the intricate functional redundancy between RB1 and the related pocket proteins RBL1/p107 and RBL2/p130 in suppressing tumorigenesis remains poorly understood. Here we performed lineage-restricted parallel inactivation of rb1 and rbl1 by multiplex CRISPR/Cas9 genome editing in the true diploid Xenopus tropicalis to gain insight into this in vivo redundancy. We show that while rb1 inactivation is sufficient to induce choroid plexus papilloma, combined rb1 and rbl1 inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimicking tp53 mutant X. tropicalis line, we demonstrate increased malignancy of rb1/rbl1-mutant glioma towards glioblastoma upon concomitant inactivation of tp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, the tp53 status had little effect on the establishment and growth of SC-PaNEC, but may rather be essential for maintaining chromosomal stability. SCLC was only rarely observed in our experimental setup, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1, generating new insights in the functional redundancy within the retinoblastoma protein family in suppressing neuroendocrine pancreatic cancer and glioma/glioblastoma. |
| Databáze: | OpenAIRE |
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