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.

Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion

“…An ordinary one-way ANOVA with a Tukey's multiple comparisons test was used to determine significance compared to PLKO.1; shPDHA1 p = 0.0006, shPDHA1 with DCA p = 0.0007. diversification of metabolic dependencies could theoretically enable invading cells to better adapt to the selective pressures of the tumor microenvironment and maintain the ability to "go" and "grow" as a cooperative unit. While metabolic heterogeneity has been observed in solid tumors 66,67 and metabolic cooperation has been described between cancer cells and the stroma [68][69][70] , this is the first report of metabolic cooperation within the lung cancer collective invasion pack.…”

Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan‐omics precision

“…Therefore, more preclinical and clinical research is urgently needed for the other RCC subtypes. In addition to modern therapeutics, the employment of contemporary molecular technologies to study human kidney cancer has blossomed in recent years, and includes transcriptomics [122][123][124][125], metabolomics [26,49,[126][127][128], multi-omics [68], radiogenomics [129], and immunogenomics [130][131][132]. All these advancements herald the promise of an upcoming pan-omics era for RCC when a confident assessment of clinically applicable predictive biomarkers becomes routine clinical practice in guiding choices of mechanism-based combination therapies to avoid treatment resistance and overcome tumor heterogeneity [1,17,133].…”

Enhancing the efficacy of glycolytic blockade in cancer cellsviaRAD51 inhibition

“…While the above experiments using PDX models give a strong indication that lung tumors relying on glycolysis will be susceptible to 2DG therapy, the heterogeneity of PDX tumors can be a confounding variable, as each PDX tumor contains multiple cell types with different glycolytic demands. 34,35 To control for this cellular heterogeneity, and to extend our findings to human B-cell cancers, we screened B-cell cancer cell lines and obtained two lines, CCRF-SB and MEC1, that share similar aerobic respiration rates but differ in their use of glycolysis as a source of energy ( Figure 3A), and yet have similar proliferation rates ex vivo ( Figure 3B). 36,37 These data allow us to hypothesize that MEC1 cells, which are more glycolysis-dependent than are CCRF-SB cells, will be more sensitive to 2DG.…”