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Molecular Cancer Research
Molecular Cancer Research
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Cancer Genes and Networks

Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers

Josh Lewis Stern, Grace Hibshman, Kevin Hu, Sarah E. Ferrara, James C. Costello, William Kim, Pablo Tamayo, Thomas R. Cech and Franklin W. Huang
Josh Lewis Stern
1BioFrontiers Institute and the Department of Biochemistry, Howard Hughes Medical Institute, University of
2Biochemistry and Molecular Genetics, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
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Grace Hibshman
1BioFrontiers Institute and the Department of Biochemistry, Howard Hughes Medical Institute, University of
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Kevin Hu
3Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Cancer Center; Bakar Computational Health Sciences Institute, Institute of Human Genetics, University of California San Francisco, San Francisco, California.
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Sarah E. Ferrara
4University of Colorado Comprehensive Cancer Center, Aurora, Colorado.
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James C. Costello
5University of Colorado, Anschutz Medical Campus, Department of Pharmacology, University of Colorado Comprehensive Cancer Center, Aurora, Colorado.
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William Kim
6Division of Medical Genetics and Center for Cancer Target Discovery and Development (CTD2), Moores Cancer Center, University of California San Diego, La Jolla, California.
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Pablo Tamayo
6Division of Medical Genetics and Center for Cancer Target Discovery and Development (CTD2), Moores Cancer Center, University of California San Diego, La Jolla, California.
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  • For correspondence: pablo.tamayo@ucsd.edu thomas.cech@colorado.edu franklin.huang@ucsf.edu
Thomas R. Cech
1BioFrontiers Institute and the Department of Biochemistry, Howard Hughes Medical Institute, University of
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  • For correspondence: pablo.tamayo@ucsd.edu thomas.cech@colorado.edu franklin.huang@ucsf.edu
Franklin W. Huang
3Division of Hematology/Oncology, Department of Medicine, Helen Diller Family Cancer Center; Bakar Computational Health Sciences Institute, Institute of Human Genetics, University of California San Francisco, San Francisco, California.
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  • For correspondence: pablo.tamayo@ucsd.edu thomas.cech@colorado.edu franklin.huang@ucsf.edu
DOI: 10.1158/1541-7786.MCR-19-1244 Published July 2020
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Abstract

In a substantial fraction of cancers TERT promoter (TERTp) mutations drive expression of the catalytic subunit of telomerase, contributing to their proliferative immortality. We conducted a pan-cancer analysis of cell lines and find a TERTp mutation expression signature dominated by epithelial-to-mesenchymal transition and MAPK signaling. These data indicate that TERTp mutants are likely to generate distinctive tumor microenvironments and intercellular interactions. Analysis of high-throughput screening tests of 546 small molecules on cell line growth indicated that TERTp mutants displayed heightened sensitivity to specific drugs, including RAS pathway inhibitors, and we found that inhibition of MEK1 and 2, key RAS/MAPK pathway effectors, inhibited TERT mRNA expression. Consistent with an enrichment of mesenchymal states in TERTp mutants, cell lines and some patient tumors displayed low expression of the central adherens junction protein E-cadherin, and we provide evidence that its expression in these cells is regulated by MEK1/2. Several mesenchymal transcription factors displayed elevated expression in TERTp mutants including ZEB1 and 2, TWIST1 and 2, and SNAI1. Of note, the developmental transcription factor SNAI2/SLUG was conspicuously elevated in a significant majority of TERTp-mutant cell lines, and knock-down experiments suggest that it promotes TERT expression.

Implications: Cancers harboring TERT promoter mutations are often more lethal, but the basis for this higher mortality remains unknown. Our study identifies that TERTp mutants, as a class, associate with a distinct gene and protein expression signature likely to impact their biological and clinical behavior and provide new directions for investigating treatment approaches for these cancers.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1050–62

  • Received December 23, 2019.
  • Revision received January 29, 2020.
  • Accepted April 7, 2020.
  • Published first April 10, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (7)
July 2020
Volume 18, Issue 7
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Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers
Josh Lewis Stern, Grace Hibshman, Kevin Hu, Sarah E. Ferrara, James C. Costello, William Kim, Pablo Tamayo, Thomas R. Cech and Franklin W. Huang
Mol Cancer Res July 1 2020 (18) (7) 1050-1062; DOI: 10.1158/1541-7786.MCR-19-1244

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Mesenchymal and MAPK Expression Signatures Associate with Telomerase Promoter Mutations in Multiple Cancers
Josh Lewis Stern, Grace Hibshman, Kevin Hu, Sarah E. Ferrara, James C. Costello, William Kim, Pablo Tamayo, Thomas R. Cech and Franklin W. Huang
Mol Cancer Res July 1 2020 (18) (7) 1050-1062; DOI: 10.1158/1541-7786.MCR-19-1244
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