RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma
| Autor: | Dieter Tulkens, Dionysia Dimitrakopoulou, Dieter Deforce, Kris Vleminckx, Christian Vanhove, Gert Van Isterdael, Rivka Noelanders, Jo Van Dorpe, Liza Eeckhout, Thomas Naert, David Creytens, Suzan Demuynck |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Retinoblastoma Cell Retinoblastoma protein Biology medicine.disease_cause medicine.disease Choroid plexus papilloma eye diseases law.invention Retinoblastoma-like protein 1 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure law 030220 oncology & carcinogenesis medicine Cancer research biology.protein Suppressor Choroid plexus Carcinogenesis 030304 developmental biology |
| DOI: | 10.1101/528299 |
| 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 compensation 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 ofrb1andrbl1by multiplex CRISPR/Cas9 genome editing in the true diploidXenopus tropicalisto gain insight into thesein vivocompensatory mechanisms. We show that whilerb1inactivation is sufficient to induce choroid plexus papilloma, combinedrb1andrbl1inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimickingtp53mutantX. tropicalisline, we demonstrate increased malignancy of retinoblastoma-mutant neural malignancies upon concomitant inactivation oftp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, thetp53status 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 set-up, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1 and generate new insights in functional compensation within the retinoblastoma protein family in suppressing pancreatic and specific neural cancers. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|