Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
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
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
- Ralph DeBerardinis, UT Southwestern Medical Center, United States
Publication history
- Received: June 12, 2018
- Accepted: March 22, 2019
- Accepted Manuscript published: March 29, 2019 (version 1)
- Accepted Manuscript updated: April 1, 2019 (version 2)
- 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
-
- 2,232
- Page views
-
- 304
- Downloads
-
- 24
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
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)
Further reading
-
- Cancer Biology
- Cell Biology
Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display upregulated cystathionine-β-synthase (CBS) expression and enhanced uptake of exogenous cysteine, which lead to increased hydrogen sulfide (H2S) and glutathione (GSH) production, consequently protecting senescent cells from oxidative stress-induced cell death. CBS depletion allows AIS cells to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production by reducing mitochondrial localized CBS while retaining antioxidant capacity of transsulfuration pathway. These findings implicate a potential tumor-suppressive role for CBS in cells with aberrant PI3K/AKT pathway activation. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.
-
- Cancer Biology
- Cell Biology
Cells encountering stressful situations activate the integrated stress response (ISR) pathway to limit protein synthesis and redirect translation to better cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely the S51 phosphorylation site of eukaryotic translation initiation factor eIF2α and genetically replaced eIF2α with eIF2α-S51A in mouse squamous cell carcinoma (SCC) stem cells of skin. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during proteotoxic stress, the ISR also functions in promoting cellular recovery once the stress has subsided. Remarkably, this molecular program is unique to transformed skin stem cells hence exposing a vulnerability in cancer that could be exploited therapeutically.