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Intratumor Heterogeneity in Primary Kidney Cancer Revealed by Metabolic Profiling of Multiple Spatially Separated Samples within Tumors.

ABSTRACT: Metabolic alteration constitutes a hallmark of cancer. Glycolysis and antioxidant pathways in kidney cancer are elevated, with frequent mutation of the VHL gene. Intratumor genetic heterogeneity has been recently demonstrated in kidney cancer. However, intratumor metabolic heterogeneity has not been investigated. Here, we used global metabolomics analysis and tissue slice tracer studies to demonstrate that different portions of a human primary kidney tumor possess different metabolic characteristics and drug sensitivity. Pyruvate levels were elevated and pyruvate metabolism was altered in some tumor sections. These observations indicated that pyruvate metabolism may constitute a possible vulnerability of kidney cancer; indeed, pyruvate stimulated the growth of primary kidney cancer cells and pharmacological inhibition of pyruvate transporters slowed the growth of patient-derived kidney tumors in mice. These findings deepen our understanding of the intratumor metabolic heterogeneity of kidney cancer and may inform novel therapeutic approaches in human kidney cancer.

SUBMITTER: Okegawa T

PROVIDER: S-EPMC5440602 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Intratumor Heterogeneity in Primary Kidney Cancer Revealed by Metabolic Profiling of Multiple Spatially Separated Samples within Tumors.

Okegawa Takatsugu T Morimoto Megumi M Nishizawa Satoru S Kitazawa Satoshi S Honda Kohei K Araki Hideo H Tamura Toshiya T Ando Ayumi A Satomi Yoshinori Y Nutahara Kikuo K Hara Takahito T

EBioMedicine 20170406

Metabolic alteration constitutes a hallmark of cancer. Glycolysis and antioxidant pathways in kidney cancer are elevated, with frequent mutation of the VHL gene. Intratumor genetic heterogeneity has been recently demonstrated in kidney cancer. However, intratumor metabolic heterogeneity has not been investigated. Here, we used global metabolomics analysis and tissue slice tracer studies to demonstrate that different portions of a human primary kidney tumor possess different metabolic characteris ...[more]

PMID: 28408240

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Project description:BackgroundCurrent bulk transcriptomic classification systems for bladder cancer do not consider the level of intratumor subtype heterogeneity.ObjectiveTo investigate the extent and possible clinical impact of intratumor subtype heterogeneity across early and more advanced stages of bladder cancer.Design setting and participantsWe performed single-nucleus RNA sequencing (RNA-seq) of 48 bladder tumors and additional spatial transcriptomics for four of these tumors. Total bulk RNA-seq and spatial proteomics data were available from the same tumors for comparison, along with detailed clinical follow-up of the patients.Outcome measurements and statistical analysisThe primary outcome was progression-free survival for non-muscle-invasive bladder cancer. Cox regression analysis, log-rank tests, Wilcoxon rank-sum tests, Spearman correlation, and Pearson correlation were used for statistical analysis.Results and limitationsWe found that the tumors exhibited varying levels of intratumor subtype heterogeneity and that the level of subtype heterogeneity can be estimated from both single-nucleus and bulk RNA-seq data, with high concordance between the two. We found that a higher class 2a weight estimated from bulk RNA-seq data is associated with worse outcome for patients with molecular high-risk class 2a tumors. The sparsity of the data generated using the DroNc-seq sequencing protocol is a limitation.ConclusionsOur results indicate that discrete subtype assignments from bulk RNA-seq data may lack biological granularity and that continuous class scores may improve clinical risk stratification of patients with bladder cancer.Patient summaryWe found that several molecular subtypes can exist within a single bladder tumor and that continuous subtype scores can be used to identify a subgroup of patients with poor outcomes. Use of these subtype scores may improve risk stratification for patients with bladder cancer, which can help in making decisions on treatment.

Project description:BackgroundIntratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.MethodsTo examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression.ResultsPhylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors.ConclusionsIntratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

Dataset Information

Intratumor Heterogeneity in Primary Kidney Cancer Revealed by Metabolic Profiling of Multiple Spatially Separated Samples within Tumors.

Publications

Intratumor Heterogeneity in Primary Kidney Cancer Revealed by Metabolic Profiling of Multiple Spatially Separated Samples within Tumors.

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