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Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

ABSTRACT: The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.

SUBMITTER: Abbott KL

PROVIDER: S-EPMC10769456 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

Abbott Keene L KL Ali Ahmed A Reinfeld Bradley I BI Deik Amy A Subudhi Sonu S Landis Madelyn D MD Hongo Rachel A RA Young Kirsten L KL Kunchok Tenzin T Nabel Christopher S CS Crowder Kayla D KD Kent Johnathan R JR Madariaga Maria Lucia L MLL Jain Rakesh K RK Beckermann Kathryn E KE Lewis Caroline A CA Clish Clary B CB Muir Alexander A Rathmell W Kimryn WK Rathmell Jeffrey C JC Vander Heiden Matthew G MG

bioRxiv : the preprint server for biology 20240408

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipid ...[more]

PMID: 38187626

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Project description:Yeast cells survive in stationary phase culture by entering quiescence, which is measured by colony-forming capacity upon nutrient re-exposure. Yeast chronological lifespan (CLS) studies, employing the comprehensive collection of gene knockout strains, have correlated weakly between independent laboratories, which is hypothesized to reflect differential interaction between the deleted genes, auxotrophy, media composition, and other assay conditions influencing quiescence. This hypothesis was investigated by high-throughput quiescence profiling of the parental prototrophic strain, from which the gene deletion strain libraries were constructed, and all possible auxotrophic allele combinations in that background. Defined media resembling human cell culture media promoted long-term quiescence and was used to assess effects of glucose, ammonium sulfate, auxotrophic nutrient availability, target of rapamycin signaling, and replication stress. Frequent, high-replicate measurements of colony-forming capacity from cultures aged past 60 days provided profiles of quiescence phenomena such as gasping and hormesis. Media acidification was assayed in parallel to assess correlation. Influences of leucine, methionine, glucose, and ammonium sulfate metabolism were clarified, and a role for lysine metabolism newly characterized, while histidine and uracil perturbations had less impact. Interactions occurred between glucose, ammonium sulfate, auxotrophy, auxotrophic nutrient limitation, aeration, TOR signaling, and/or replication stress. Weak correlation existed between media acidification and maintenance of quiescence. In summary, experimental factors, uncontrolled across previous genome-wide yeast CLS studies, influence quiescence and interact extensively, revealing quiescence as a complex metabolic and developmental process that should be studied in a prototrophic context, omitting ammonium sulfate from defined media, and employing highly replicable protocols.

Project description:BackgroundTranscriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. Renal cell carcinoma (RCC) is the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. Despite intensive study, novel therapeutic strategies to target RCC have been difficult to develop. Since the RCC epigenome is relatively understudied, we sought to elucidate key mechanisms underpinning the tumor phenotype and its clinical behavior.MethodsWe performed genome-wide chromatin accessibility (DNase-seq) and transcriptome profiling (RNA-seq) on paired tumor/normal samples from 3 patients undergoing nephrectomy for removal of RCC. We incorporated publicly available data on HIF binding (ChIP-seq) in a RCC cell line. We performed integrated analyses of these high-resolution, genome-scale datasets together with larger transcriptomic data available through The Cancer Genome Atlas (TCGA).FindingsThough HIF transcription factors play a cardinal role in RCC oncogenesis, we found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding near their gene body. Examination of chromatin accessibility profiles revealed that some of these transcription factors influenced the tumor's regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Elevated POU5F1 transcript levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Unexpectedly, we discovered a HIF-pathway-responsive promoter embedded within a endogenous retroviral long terminal repeat (LTR) element at the transcriptional start site of the PSOR1C3 long non-coding RNA gene upstream of POU5F1. RNA transcripts are induced from this promoter and read through PSOR1C3 into POU5F1 producing a novel POU5F1 transcript isoform. Rather than being unique to the POU5F1 locus, we found that HIF binds to several other transcriptionally active LTR elements genome-wide correlating with broad gene expression changes in RCC.InterpretationIntegrated transcriptomic and epigenomic analysis of matched tumor and normal tissues from even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes. Several transcription factors appear to act downstream of HIF including the potent stem cell transcription factor POU5F1. Dysregulated expression of POU5F1 is part of a larger pattern of gene expression changes in RCC that may be induced by HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs.

Project description:Bilateral renal clear cell carcinoma (BRCC) is a rare type of renal cell carcinoma (RCC) that accounts for only 1-5% of RCC cases and has a poor clinical prognosis. The origin, tumor microenvironment, cellular molecular features, and intra-tumoral heterogeneity of BRCC are still unclear. We downloaded BRCC single-cell transcriptome sequencing data from the gene expression omnibus database biochip GSE171306, containing 3,575 cells from left-sided clear cell renal cell carcinoma (ccRCC) and 3,568 cells from right-sided ccRCC, and used a series of R packages for data quality control (QC) and subsequent analysis of BRCC single-cell transcriptome data, including the use of the R packages Seurat and scCancer for cell QC, identification of major cell types, and cell annotation; R package scran for calculation of cell cycle scores; R package infercnv for malignancy scoring of tumor cells; R package ReactomeGSA for functional enrichment analysis; R package Monocle 2 for the analysis of cell differentiation trajectories; and R package CellphoneDB for the analysis of intercellular interactions. In this study, by analyzing the high-quality single-cell transcriptome data of BRCC, we identified 18 cell types and found that left- and right-sided ccRCC were approximately the same in terms of cell type and the number of each cell but differed significantly in terms of tumor cell malignancy score, tumor microenvironment, and cell stemness score. In the cell differentiation trajectory analysis of BRCC, we found that endothelial cells and macrophages play an extremely important role in its tumor progression. Further cell communication analysis was performed, and we found that it may signal through ligand-receptors, such as vascular endothelial growth factor-vascular endothelial growth factor receptor1 (VEGF-VEGFR1), MIF-(CD74-CXCR4), and growth arrest-specific protein 6-AXL, to influence the development of BRCC. The analysis of single-cell transcriptomic data of human BRCC suggests that left- and right-sided ccRCC may be of the same tumor origin, but the left-sided ccRCC is more malignant and has a better immune response.

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Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

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Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

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