Transcriptomic and metabolomic profiles in renal cell carcinoma (RCC) tumors reflect ontogeny of RCC subtypes

Introduction The renal cell carcinoma (RCC) subtypes clear cell RCC (ccRCC), papillary RCC (papRCC) and chromophobe RCC (chRCC) are proposed to arise from distinct cell types of the nephron. The subtypes differ not only in their incidence, but also in terms of metastasis risk and prognosis. The most common form ccRCC, accounting for ~75% of the cases, is characterized by reprogramming of tumor metabolism and is therefore assumed to be a metabolic disease. In contrast, little is known about the metabolic alterations in non-ccRCC subtypes. In this study, we applied transcriptomics and metabolomics profiling to identify key pathways altered in specific RCC subtypes and in ccRCC-derived metastases. In addition, the potential of metabolites to improve subtype classification and to identify promising drug targets for new therapeutic interventions was elucidated. Experimental Procedures Genome-wide expression analyses were performed in ccRCC (n=58), chRCC (n=19), papRCC (n=14), matching non-tumor tissues, and ccRCC-derived metastases (n=9) using HTA 2.0 gene expression arrays. The transcriptomic profiles were compared to expression data of RCC cohorts of TCGA (KIRC, n=452; KIRP, n=260; KICH, n=59). In addition, a targeted metabolomics approach using LC/MS technology was applied in these tissues. Results Pathway enrichment analyses based on metabolic gene expression signatures revealed metabolic alterations in proximal vs. distal cells of the nephron. Accordingly, the respective RCC subtypes arising from proximal (ccRCC, papRCC) or distal (chRCC) tubular cells showed major differences in transcriptional activity of metabolic pathways, reflecting their cell type of origin. Based on metabolite levels, hierarchical cluster analyses separated the samples into three groups, differentiating non-tumor tissues, chRCC, as well as ccRCC, ccRCC-derived metastases and papRCC, indicating differences depending on RCC ontogeny also for metabolic profiles. ccRCC-derived metastases clustered with primary ccRCC tumors, irrespective of affected organs. When comparing ccRCC and chRCC subtypes, major differences were found, e.g. for certain biogenic amines of the polyamine pathway. Differential regulation of this pathway was also reflected on transcriptome level. In vitro experiments revealed that interfering with the polyamine pathway by inhibiting the ornithine-decarboxylase with difluoromethylornithine, reduced cell viability and mitochondrial activity in RCC cells. Conclusion In this study, we elucidated the transcriptomic and metabolomic profiles of RCC tumors, which confirm the distinct ontogeny of RCC subtypes from different parts of the nephron. Furthermore, we found that identification and quantification of differentially regulated metabolites can improve RCC classification and represent an attractive opportunity to reveal subtype-specific therapeutic targets. Citation Format: Pascale Fisel, Florian Buttner, Anna Reustle, Verena Klumpp, Stefan Winter, Steffen Rausch, Jorg Hennenlotter, Stephan Kruck, Arnulf Stenzl, Judith Wahrheit, Denise Sonntag, Marcus Scharpf, Falko Fend, Abbas Agaimy, Arndt Hartmann, Jens Bedke, Matthias Schwab, Elke Schaeffeler. Transcriptomic and metabolomic profiles in renal cell carcinoma (RCC) tumors reflect ontogeny of RCC subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3485.