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RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis

Thomas Naert (UGent) , Dionysia Dimitrakopoulou (UGent) , Dieter Tulkens (UGent) , Suzan Demuynck (UGent) , Marjolein Carron (UGent) , Rivka Noelanders (UGent) , Liza Eeckhout, Gert Van Isterdael (UGent) , Dieter Deforce (UGent) , Christian Vanhove (UGent) , et al.
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Abstract
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.
Keywords
Genetics, Cancer Research, Molecular Biology, RETINOBLASTOMA PROTEIN, GENOMIC PROFILES, HIGH-GRADE, BETA-CELL, P53, INACTIVATION, TP53, DELETION, MICE, PRB

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MLA
Naert, Thomas, et al. “RBL1 (P107) Functions as Tumor Suppressor in Glioblastoma and Small-Cell Pancreatic Neuroendocrine Carcinoma in Xenopus Tropicalis.” ONCOGENE, 2020.
APA
Naert, T., Dimitrakopoulou, D., Tulkens, D., Demuynck, S., Carron, M., Noelanders, R., … Vleminckx, K. (2020). RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis. ONCOGENE.
Chicago author-date
Naert, Thomas, Dionysia Dimitrakopoulou, Dieter Tulkens, Suzan Demuynck, Marjolein Carron, Rivka Noelanders, Liza Eeckhout, et al. 2020. “RBL1 (P107) Functions as Tumor Suppressor in Glioblastoma and Small-Cell Pancreatic Neuroendocrine Carcinoma in Xenopus Tropicalis.” ONCOGENE.
Chicago author-date (all authors)
Naert, Thomas, Dionysia Dimitrakopoulou, Dieter Tulkens, Suzan Demuynck, Marjolein Carron, Rivka Noelanders, Liza Eeckhout, Gert Van Isterdael, Dieter Deforce, Christian Vanhove, Jo Van Dorpe, David Creytens, and Kris Vleminckx. 2020. “RBL1 (P107) Functions as Tumor Suppressor in Glioblastoma and Small-Cell Pancreatic Neuroendocrine Carcinoma in Xenopus Tropicalis.” ONCOGENE.
Vancouver
1.
Naert T, Dimitrakopoulou D, Tulkens D, Demuynck S, Carron M, Noelanders R, et al. RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis. ONCOGENE. 2020;
IEEE
[1]
T. Naert et al., “RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis,” ONCOGENE, 2020.
@article{8645796,
  abstract     = {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.},
  author       = {Naert, Thomas and Dimitrakopoulou, Dionysia and Tulkens, Dieter and Demuynck, Suzan and Carron, Marjolein and Noelanders, Rivka and Eeckhout, Liza and Van Isterdael, Gert and Deforce, Dieter and Vanhove, Christian and Van Dorpe, Jo and Creytens, David and Vleminckx, Kris},
  issn         = {0950-9232},
  journal      = {ONCOGENE},
  keywords     = {Genetics,Cancer Research,Molecular Biology,RETINOBLASTOMA PROTEIN,GENOMIC PROFILES,HIGH-GRADE,BETA-CELL,P53,INACTIVATION,TP53,DELETION,MICE,PRB},
  language     = {eng},
  pages        = {15},
  title        = {RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis},
  url          = {http://dx.doi.org/10.1038/s41388-020-1173-z},
  year         = {2020},
}

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