Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
- Memorial Sloan Kettering Cancer Center, United States
- University of Michigan, United States
- Baylor College of Medicine, United States
- University of Washington, United States
- Ludwig-Maximilians University, Germany
- Metabolon Inc, United States
- Cedars-Sinai Medical Center, United States
- Dana-Farber Cancer Institute, United States
- Washington University in St Louis, United States
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
Abraham Ari Hakimi
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.
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
-
- 2,541
- views
-
- 339
- downloads
-
- 38
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
eLife 8:e38986.
https://doi.org/10.7554/eLife.38986
Further reading
-
- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
-
- Cancer Biology
- Immunology and Inflammation
In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.
