LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy
Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley
Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley
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Research Article Oncology

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy

Abstract

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7–independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Authors

Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley

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Figure 1

LIN28B mediates features of aggressive disease in a MYCN-driven model system in vivo.

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LIN28B mediates features of aggressive disease in a MYCN-driven model sy...
(A) Representative bioluminescence images 4 weeks after injection of luciferase-expressing BE2C cells of the indicated genotypes into the tail vein of immunocompromised mice (NSG). n = 5 for BE2C control (CTRL1 gRNA) and n = 5 for BE2C KO (EX3.1 gRNA). (B) Quantitative analysis of bioluminescence of mice used in A. n = 5/specific gRNA (CTRL1/2 for CTRL; EX2 and EX3.1 for KO), n = 10/group. (C) Kaplan-Meier survival curve of NSG mice injected with 100,000 BE2C cells of the indicated genotypes. n = 5/specific gRNA (CTRL1/2 for CTRL; EX2 and EX3.1 for KO), n = 10/group. (D) Kaplan-Meier survival curve of NSG mice injected with 100,000 Kelly cells of the indicated genotypes. n = 5/specific gRNA (CTRL1/2 for CTRL; EX2 and EX3.1 for KO), n = 10/group. (E) Limiting-dilution tail vein injection assay of BE2C cells infected with a modified V2 CRISPR/Cas9 lentivirus expressing mCherry (CTRL1 [CTRL] vs. EX3.1 [KO] gRNA; n = 5/mice per dilution). All statistical data were assessed using log-rank (Mantel-Cox) test (C and D) and 2-tailed Student’s t test (B) and are presented as mean ± SEM. *P < 0.05; ***P < 0.001; ****P < 0.0001.