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 Sy Lee; Daniel Dominguez; David T Ting; George Q Daley

doi:10.1172/JCI145142

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

J Clin Invest. 2021 Nov 15;131(22):e145142. doi: 10.1172/JCI145142.

Authors

Pavlos Missios^{1

2

3}, Edroaldo Lummertz da Rocha^{1

2

3

4}, Daniel S Pearson^{1

2

3}, Julia Philipp^{5

6}, Maria M Aleman⁷, Mehdi Pirouz^{1

2

8}, Dorian Farache^{9

10}, Joseph W Franses⁵, Caroline Kubaczka^{1

2

3}, Kaloyan M Tsanov^{1

2

3}, Deepak K Jha^{1

2

3}, Brian Pepe-Mooney^{1

2}, John T Powers^{1

2

3}, Richard I Gregory^{1

2

3

11

12}, Amy Sy Lee^{9

10}, Daniel Dominguez^{7

13}, David T Ting⁵, George Q Daley^{1

2

3}

Affiliations

¹ Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
² Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, USA.
³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
⁴ Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil.
⁵ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, Tübingen, Germany.
⁷ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁸ Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA.
⁹ Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹¹ Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
¹² Harvard Initiative for RNA Medicine, Boston, Massachusetts, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.

Keywords: Cancer; Cell migration/adhesion; Oncology; Translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Humans
N-Myc Proto-Oncogene Protein / physiology*
Neoplasm Metastasis*
Neuroblastoma / etiology
Neuroblastoma / pathology*
RNA-Binding Proteins / physiology*
Ribosomes / physiology*

Substances

LIN28B protein, human
MYCN protein, human
N-Myc Proto-Oncogene Protein
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding