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

摘要

Highlights ? Human primary kidney tumors harbor intratumor metabolic heterogeneity. ? Some tumor portions have high pyruvate levels with low glycolysis metabolites. ? Different pyruvate metabolic pathways are present in a tumor and represent a potential vulnerability Understanding the features of cancer can lead to effective cancer therapy. One of the reasons why anti-cancer drugs have limited efficacy is the existence of intratumor heterogeneity. Intratumor heterogeneity is usually revealed by diverse genetic alterations. In this study, we studied metabolic features to comprehend intratumor heterogeneity. In human primary kidney tumors, some portions contained high levels of upper-glycolysis metabolites; however, other portions contained high pyruvate levels. Difference in pyruvate metabolism was observed in a tumor. Additional studies suggested that pyruvate metabolism represented a vulnerability in kidney cancer. 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.