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Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

ABSTRACT: BACKGROUNDClear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinctive metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC, with unknown effects on tumor pathobiology.METHODSWe investigated the landscape of ccRCCs and paired normal kidney tissues using integrated transcriptomic, metabolomic, and metallomic approaches in a cohort of white males who were long-term current smokers (LTS) or were never smokers (NS).RESULTSAll 3 Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OXPHOS) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine, and histidine. Cadmium, copper, and inorganic arsenic accumulated in LTS tumors, showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. A gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas ccRCC tumors that was independent of genomic alterations.CONCLUSIONThe work identified the TS-related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OXPHOS status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC, highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.FUNDINGDepartment of Defense, Veteran Administration, NIH, ACS, and University of Cincinnati Cancer Institute.

SUBMITTER: Reigle J

PROVIDER: S-EPMC7773408 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

Reigle James J Secic Dina D Biesiada Jacek J Wetzel Collin C Shamsaei Behrouz B Chu Johnson J Zang Yuanwei Y Zhang Xiang X Talbot Nicholas J NJ Bischoff Megan E ME Zhang Yongzhen Y Thakar Charuhas V CV Gaitonde Krishnanath K Sidana Abhinav A Bui Hai H Cunningham John T JT Zhang Qing Q Schmidt Laura S LS Linehan W Marston WM Medvedovic Mario M Plas David R DR Figueroa Julio A Landero JAL Meller Jarek J Czyzyk-Krzeska Maria F MF

The Journal of clinical investigation 20210101 1

BACKGROUNDClear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinctive metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC, with unknown effects on tumor pathobiology.METHODSWe investigated the landscape of ccRCCs and paired normal kidney tissues using integrated transcriptomic, metabol ...[more]

PMID: 32970633

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Project description:Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Project description:BackgroundMetabolism reprogramming is a hallmark that associates tumor growth, metastasis, progressive, and poor prognosis. However, the metabolism-related molecular patterns and mechanism in clear cell renal cell carcinoma (ccRCC) remain unclear. Herein, the purpose of this study was to identify metabolism-related molecular pattern and to investigate the characteristics and prognostic values of the metabolism-related clustering.MethodsWe comprehensively analyzed the differentially expressed genes (DEGs), and metabolism-related genes (MAGs) in ccRCC based on the TCGA database. Consensus clustering was used to construct a metabolism-related molecular pattern. Then, the biological function, molecular characteristics, Estimate/immune/stomal scores, immune cell infiltration, response to immunotherapy, and chemotherapy were analyzed. We also identified the DEGs between subclusters and constructed a poor signature and risk model based on LASSO regression cox analysis and univariable and multivariable cox regression analyses. Then, a predictive nomogram was constructed and validated by calibration curves.ResultsA total of 1942 DEGs (1004 upregulated and 838 downregulated) between ccRCC tumor and normal samples were identified, and 254 MRGs were screened out from those DEGs. Then, 526 ccRCC patients were divided into two subclusters. The 7 metabolism-related pathways enriched in cluster 2. And cluster 2 with high Estimate/immune/stomal scores and poor survival. While, cluster 1 with higher immune cell infiltrating, expression of the immune checkpoint, IFN, HLA, immune activation-related genes, response to anti-CTLA4 treatment, and chemotherapy. Moreover, we identified 295 DEGs between two metabolism-related subclusters and constructed a 15-gene signature and 9 risk factors. Then, a risk score was calculated and the patients into high- and low-risk groups in TCGA-KIRC and E-MTAB-1980 datasets. And the prediction viability of the risk score was validated by ROC curves. Finally, the clinicopathological characteristics (age and stage), risk score, and molecular clustering, were identified as independent prognostic variables, and were used to construct a nomogram for 1-, 3-, 5-year overall survival predicting. The calibration curves were used to verify the performance of the predicted ability of the nomogram.ConclusionOur finding identified two metabolism-related molecular subclusters for ccRCC, which facilitates the estimation of response to immunotherapy and chemotherapy, and prognosis after treatment.

Project description:Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness. In this study, we examined the effects of cigarette smoke-exposed CAFs on metabolic coupling and tumor aggressiveness of HNSCC. Cigarette smoke (CS) extract was generated by dissolving cigarette smoke in growth media. Fibroblasts were cultured in CS or control media. HNSCC cells were cocultured in vitro and coinjected in vivo with CS or control fibroblasts. We found that CS induced oxidative stress, glycolytic flux and MCT4 expression, and senescence in fibroblasts. MCT4 upregulation was critical for fibroblast viability under CS conditions. The effects of CS on fibroblasts were abrogated by antioxidant treatment. Coculture of carcinoma cells with CS fibroblasts induced metabolic coupling with upregulation of the marker of glycolysis MCT4 in fibroblasts and markers of mitochondrial metabolism MCT1 and TOMM20 in carcinoma cells. CS fibroblasts increased CCL2 expression and macrophage migration. Coculture with CS fibroblasts also increased two features of carcinoma cell aggressiveness: resistance to cell death and enhanced cell migration. Coinjection of carcinoma cells with CS fibroblasts generated larger tumors with reduced apoptosis than control coinjections, and upregulation of MCT4 by CS exposure was a driver of these effects. We demonstrate that a tumor microenvironment exposed to CS is sufficient to modulate metabolism and cancer aggressiveness in HNSCC. IMPLICATIONS: CS shifts cancer stroma toward glycolysis and induces head and neck cancer aggressiveness with a mitochondrial profile linked by catabolite transporters and oxidative stress. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/17/9/1893/F1.large.jpg.

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Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

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Tobacco smoking induces metabolic reprogramming of renal cell carcinoma.

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