1. Cancer Biology
  2. Genetics and Genomics
Download icon

Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma

  1. Jianing Xu
  2. Eduard Reznik  Is a corresponding author
  3. Ho-Joon Lee
  4. Gunes Gundem
  5. Philip Jonsson
  6. Judy Sarungbam
  7. Anna Bialik
  8. Francisco Sanchez-Vega
  9. Chad J Creighton
  10. Jake G Hoekstra
  11. Li Zhang
  12. Peter Sajjakulnukit
  13. Daniel Kremer
  14. Zachary P Tolstyka
  15. Jozefina Casuscelli
  16. Steve Stirdivant
  17. Jie Tang
  18. Nikolaus Schultz
  19. Paul S Jeng
  20. Yiyu Dong
  21. Wenjing Su
  22. Emily H-Y Cheng
  23. Paul Russo
  24. Jonathan A Coleman
  25. Elli Papaemmanuil
  26. Ying-Bei Chen
  27. Victor E Reuter
  28. Chris Sander
  29. Scott R Kennedy
  30. James J Hsieh
  31. Costas Lyssiotis  Is a corresponding author
  32. Satish K Tickoo  Is a corresponding author
  33. Abraham Ari Hakimi  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. University of Michigan, United States
  3. Baylor College of Medicine, United States
  4. University of Washington, United States
  5. Ludwig-Maximilians University, Germany
  6. Metabolon Inc, United States
  7. Cedars-Sinai Medical Center, United States
  8. Dana-Farber Cancer Institute, United States
  9. Washington University in St Louis, United States
Research Article
  • Cited 16
  • Views 2,010
  • Annotations
Cite this article as: eLife 2019;8:e38986 doi: 10.7554/eLife.38986

Abstract

While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.

Article and author information

Author details

  1. Jianing Xu

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  2. Eduard Reznik

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    reznike@mskcc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6511-5947
  3. Ho-Joon Lee

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  4. Gunes Gundem

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  5. Philip Jonsson

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  6. Judy Sarungbam

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  7. Anna Bialik

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  8. Francisco Sanchez-Vega

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Chad J Creighton

    Department of Medicine, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Jake G Hoekstra

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  11. Li Zhang

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  12. Peter Sajjakulnukit

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  13. Daniel Kremer

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  14. Zachary P Tolstyka

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  15. Jozefina Casuscelli

    Department of Urology, Ludwig-Maximilians University, Munich, Germany
    Competing interests
    No competing interests declared.
  16. Steve Stirdivant

    Metabolon Inc, Durham, United States
    Competing interests
    Steve Stirdivant, This author is a former employee of Metabolon, Inc..
  17. Jie Tang

    Genomics Core, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States
    Competing interests
    No competing interests declared.
  18. Nikolaus Schultz

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  19. Paul S Jeng

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  20. Yiyu Dong

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  21. Wenjing Su

    Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  22. Emily H-Y Cheng

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  23. Paul Russo

    Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  24. Jonathan A Coleman

    Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  25. Elli Papaemmanuil

    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  26. Ying-Bei Chen

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5207-3648
  27. Victor E Reuter

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  28. Chris Sander

    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  29. Scott R Kennedy

    Department of Pathology, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  30. James J Hsieh

    Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University in St Louis, St Louis, United States
    Competing interests
    No competing interests declared.
  31. Costas Lyssiotis

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    For correspondence
    clyssiot@med.umich.edu
    Competing interests
    No competing interests declared.
  32. Satish K Tickoo

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    tickoos@mskcc.org
    Competing interests
    No competing interests declared.
  33. Abraham Ari Hakimi

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    hakimia@mskcc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0930-8824

Funding

Damon Runyon Cancer Research Foundation (Dale F. Frey Award for Breakthrough Scientists DFS-09-14)

  • Costas Lyssiotis

Sidney Kimmel Foundation for Cancer Research (Sidney Kimmel Center for Prostate and Urologic Cancers)

  • Abraham Ari Hakimi

American Urological Association (Research Scholar Award)

  • Abraham Ari Hakimi

V Foundation for Cancer Research (Junior Scholar Award V2016-009)

  • Costas Lyssiotis

Sidney Kimmel Foundation for Cancer Research (Kimmel Scholar Award SKF-16-005)

  • Costas Lyssiotis

National Institutes of Health (DK097153)

  • Costas Lyssiotis

Charles Woodson Research Fund

  • Costas Lyssiotis

the UM Pediatric Brain Tumor Initiative

  • Costas Lyssiotis

University of Michigan's Program in Chemical Biology (Graduate Assistance in Areas of National Need (GAANN) award)

  • Daniel Kremer

National Cancer Institute (P30 CA008748)

  • Jianing Xu
  • Eduard Reznik
  • Gunes Gundem
  • Philip Jonsson
  • Judy Sarungbam
  • Anna Bialik
  • Francisco Sanchez-Vega
  • Jozefina Casuscelli
  • Nikolaus Schultz
  • Yiyu Dong
  • Paul Russo
  • Jonathan A Coleman
  • Elli Papaemmanuil
  • Ying-Bei Chen
  • Victor E Reuter
  • Chris Sander
  • Satish K Tickoo
  • Abraham Ari Hakimi

National Cancer Institute (P30 CA046592)

  • Costas Lyssiotis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Frozen samples and genomic data were acquired through MSKCC IRB approved tissue protocol 06-107.

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: June 12, 2018
  2. Accepted: March 22, 2019
  3. Accepted Manuscript published: March 29, 2019 (version 1)
  4. Accepted Manuscript updated: April 1, 2019 (version 2)
  5. Version of Record published: April 11, 2019 (version 3)

Copyright

© 2019, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,010
    Page views
  • 268
    Downloads
  • 16
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Computational and Systems Biology
    Kenichi Shimada et al.
    Tools and Resources Updated

    Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover these gene dependencies in hundreds of cancer cell lines. To make this drug discovery resource more accessible to the scientific community, we built an easy-to-use browser, shinyDepMap (https://labsyspharm.shinyapps.io/depmap). shinyDepMap combines CRISPR and shRNA data to determine, for each gene, the growth reduction caused by knockout/knockdown and the selectivity of this effect across cell lines. The tool also clusters genes with similar dependencies, revealing functional relationships. shinyDepMap can be used to (1) predict the efficacy and selectivity of drugs targeting particular genes; (2) identify maximally sensitive cell lines for testing a drug; (3) target hop, that is, navigate from an undruggable protein with the desired selectivity profile, such as an activated oncogene, to more druggable targets with a similar profile; and (4) identify novel pathways driving cancer cell growth and survival.

    1. Cancer Biology
    2. Neuroscience
    Zhi Zhang et al.
    Research Article

    Adjuvant tamoxifen therapy improves survival in breast cancer patients. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are unclear. Here, we show that mice undergoing tamoxifen treatment experience changes in temperature, bone, and movement. Single-cell RNA sequencing reveals that tamoxifen treatment induces widespread gene expression changes in the hypothalamus and preoptic area (hypothalamus-POA). These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus-POA ablates or reverses tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit tamoxifen-induced changes in temperature, bone, or movement. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus-POA and indicate that ERα mediates several physiological effects of tamoxifen treatment in mice.