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Oncogene
2020 Mar 01;3913:2692-2706. doi: 10.1038/s41388-020-1173-z.
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RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis.
Naert T
,
Dimitrakopoulou D
,
Tulkens D
,
Demuynck S
,
Carron M
,
Noelanders R
,
Eeckhout L
,
Van Isterdael G
,
Deforce D
,
Vanhove C
,
Van Dorpe J
,
Creytens D
.
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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.
Fig. 1: Tp53 mutant X. tropicalis develop hematological malignancy and sarcomas.
a Kaplan–Meier survival analysis on cohorts consisting of two clutches of tp53 homozygous knockout (n = 6; red and n = 7; blue) and one clutch of heterozygous tp53 knockout (n = 14; black) X. tropicalis. Statistical analysis was done using the Prism Mantel–Cox test (ns not significant; **p < 0.01; ***p < 0.001). Chi-Squared values and the Hazard ratios are listed in Supplementary table 2A. b X-ray imaging of a 28-month old tp53+/δ4var2 demonstrating ectopic calcified structures (white arrows). c (Left panels) In the wild-type spleen, CD3+ T-cells form a ring-like structure around the PCNA+ B-cells located in the white pulp. (Right panels) Disruption of a normal CD3+ ring-like structure observed in a tp53δ4var2/δ4var2 animal is indicative of hematological malignancy. d Pie chart summarizing the observed splenic immunostaining for CD3 and PCNA in tp53δ4var1/δ4var2 animals. Staining patterns being either normal or with loss of the typical CD3+ ring structure (CD3) with or without ectopic staining of PCNA (CD3/PCNA) in the red pulp. e Photomicrograph of Natt–Herrick stained blood demonstrating a cluster of leukocytes and a normal nucleated erythrocyte. Inset demonstrates a high-magnification photomicrograph of a lymphoblast. f Flow cytometry analysis reveals an increased number of both CD3+ (left) and CD8+ lymphoblasts (right) in peripheral blood of a tp53δ4var1/δ4var2 animal, when compared with an age-matched control. g Histopathology of the liver reveals diffuse infiltration of T-lymphoblasts, also enriched within the livercapillary (white arrow; top inset) and in between the liver parenchymal cells (black arrow; bottom inset). h Sarcoma in a tp53+/δ4var2 animal observed upon gross examination, with associated histopathology and demonstration of malignant nature by PCNA proliferation staining. White scale bar is 100 µm and black scale bar is 5 µM.
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