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. Ed 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 18
  • Views 2,063
  • 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.

Data availability

The new data generated in this study is primarily tumor/germline sequencing of primary human tumor specimens, and constitutes human subject data. To protect the privacy of the human subjects, we have included somatic mutation calls in Figure 4 Source Data 1, but have withheld germline information. Source data have been provided for Figures 1-5. Controlled access for TCGA sequencing data (RNA-sequencing and whole exome sequencing of CCPAP tumors) are available via GDC commons data portal (https://gdc.cancer.gov/) by querying the 5 CCPAP sample IDs (BP-4760, BP-4784, BP-4795, DV-5567, BP-4177). Data from the The Cancer Genome Atlas Pan-Cancer Analysis Project related to this studied can be downloaded directly from firebrowse.org at the url http://gdac.broadinstitute.org/runs/stddata__2016_01_28/data/KIPAN/20160128/.

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. Ed 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
  • Ed 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

  • 2,063
    Page views
  • 279
    Downloads
  • 18
    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)

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Chromosomes and Gene Expression

    Single-PanIN-seq unveils that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence

    Shou Liu et al.
    Research Article

    ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here, we identified the anti-senescence effect of Arid1a deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in a mouse model. In a human cell line model, we found that ARID1A deficiency upregulates the expression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), which plays an essential role in attenuating the senescence induced by oncogenic KRAS through scavenging reactive oxygen species (ROS). As a subunit of the SWI/SNF chromatin remodeling complex, our ATAC sequencing data showed that ARID1A deficiency increases the accessibility of the enhancer region of ALDH1A1. This study provides the first evidence that ARID1A deficiency promotes pancreatic tumorigenesis by attenuating KRAS-induced senescence through the upregulation of ALDH1A1 expression.

    1. Cancer Biology
    2. Cell Biology

    A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma

    Alvaro Gonzalez Rajal et al.
    Research Advance

    We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

    1. Cancer Biology

    Limited inhibition of multiple nodes in a driver network blocks metastasis

    Ali Ekrem Yesilkanal et al.
    Research Article

    Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment.