Host organ environment shapes clear cell renal cell carcinoma metastatic metabolism

Primary clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic rewiring which adapts as tumors evolve to become more aggressive, yet the evidence showing whether those programs are preserved versus reshaped at distant metastatic sites in humans remains limited. To investigate the determinants of ccRCC metastatic metabolism, we performed mass-spectrometry-based metabolomic profiling on quartets of primary tumor, adjacent normal kidney, distant metastasis, and normal adjacent to metastasis, from 14 patients with metachronous metastases. We find three key results. First, through unpaired comparisons of ccRCC metastases versus primaries, we observe decreases in glutathione metabolism in metastatic tissues. Second, using linear models, we find that metabolic profiles of metastatic tumors more closely resemble those of the normal tissue at the metastatic site than those of the patient's original kidney tumor. Third, we show that several metabolites in metastases can be approximated as simple mixtures of the primary tumor and the local normal tissue. Together, these results suggest that ccRCC metastases are strongly reshaped by the metabolic environment of the metastatic organ.