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Metabolic evaluation of sporadic papillary kidney cancer.

377 Background: Papillary kidney cancer, which occurs in 15% of patients with kidney cancer, can be aggressive and there is currently no effective form of therapy for this disease. To evaluate the metabolic characteristics of sporadic papillary kidney cancer, we have evaluated metabolic parameters of several papillary kidney cancer cell lines and available gene expression profiles.


METHODS
Established cell lines derived from patients with sporadic papillary kidney cancer (LABAZ, MDACC-55, HRC-86T2) and from a hereditary form of fumarate hydratase-deficient kidney cancer (UOK262) were evaluated. All sporadic lines were initially sequenced for fumarate hydratase (FH). All cell lines were metabolically profiled using the Seahorse Extracellular Flux Analyzer and further evaluated for reactive oxygen species (ROS), mitochondrial membrane potential, and glucose dependence. Finally gene expression profiles of publically available datasets of papillary and HLRCC tumors were downloaded, normalized, and analyzed.


RESULTS
Sporadic lines had no alterations in FH and metabolic analysis demonstrated normal oxygen consumption and minimal lactate production, in contrast to highly glycolytic UOK262. Also unlike UOK262, the sporadic papillary kidney cancer lines were not sensitive to glucose withdrawal, had low levels of ROS, and had normal mitochondria membrane potential. Principal component analysis (PCA) demonstrated that HLRCC tumor specimens are very different from sporadic papillary tumors at the molecular level.


CONCLUSIONS
Our study of established sporadic papillary RCC and fumarate hydratase-deficient HLRCC cell line together with analysis of available gene expression profiles demonstrates that these sporadic papillary kidney cancer cell lines appear to have a distinct metabolic profile from those in the fumarate hydratase deficient kidney cancer cell line. Understanding the metabolic basis of papillary kidney cancer could provide the foundation for the development of targeted approaches to therapy for patients with this disease.