Most kidney cancers are metabolically dysfunctional^1–4, but how this dysfunction affects cancer progression in humans is unknown. We infused ¹³C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-¹³C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-¹³C]acetate and [U-¹³C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

Beyond their pulmonary disease, many COVID-19 patients experience a complex constellation of characteristics, including hyperinflammatory responses, autoimmune disorders, and coagulopathies. However, the pathogenesis of these aspects of COVID-19 is obscure. More than 90% of people are latently infected with the lymphotropic herpesviruses Epstein–Barr Virus (EBV) and/or Human Herpesvirus-6 (HHV-6). Some of the inflammatory features of COVID-19 resemble clinical syndromes seen during EBV and HHV-6 infection, and these latent viruses can be reactivated by inflammatory mediators. We hypothesized that EBV and HHV-6 reactivation might be a common feature of early COVID-19, particularly in patients with more inflammation. We tested for EBV and HHV-6 reactivation in 67 patients acutely hospitalized with COVID-19 using previously validated quantitative PCR assays on the plasma. In our cohort, we found that 15/67 (22.4%) patients had detectable EBV and 3/67 (4.5%) had detectable HHV-6. This frequency of activation is somewhat more than the frequency reported for some healthy cohorts, such as blood donors and other healthy control cohorts. There was no association between EBV or HHV-6 and markers indicative of more inflammatory disease. We conclude that EBV and HHV-6 activation at about day 7 of hospitalization occurred in a modest fraction of our cohort of COVID-19 patients and was not associated with high levels of inflammation. In the modest fraction of patients, EBV and HHV-6 reactivation could contribute to some features of acute disease and pre-disposition to post-acute sequelae in a subset of patients.

Summary: Most kidney cancers display evidence of metabolic dysfunction ^1–4 but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse ¹³ C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U- ¹³ C]glucose varies across cancer subtypes, indicating that the kidney environment alone cannot account for all metabolic reprogramming in these tumours. Compared to the adjacent kidney, clear cell renal cell carcinomas (ccRCC) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in organotypic slices cultured ex vivo, indicating that suppressed labeling is tissue intrinsic. Infusions of [1,2- ¹³ C]acetate and [U- ¹³ C]glutamine in patients, coupled with respiratory flux of mitochondria isolated from kidney and tumour tissue, reveal primary defects in mitochondrial function in human ccRCC. However, ccRCC metastases unexpectedly have enhanced labeling of TCA cycle intermediates compared to primary ccRCCs, indicating a divergent metabolic program during ccRCC metastasis in patients. In mice, stimulating respiration in ccRCC cells is sufficient to promote metastatic colonization. Altogether, these findings indicate that metabolic properties evolve during human kidney cancer progression, and suggest that mitochondrial respiration may be limiting for ccRCC metastasis but not for ccRCC growth at the site of origin.

PURPOSE: Increased heterogeneity in outcomes has been observed postnephrectomy in patients with renal cell carcinoma (RCC), with standard clinical parameters being primarily used for risk assessment. Currently, no blood-based biomarkers are available for molecular residual disease (MRD) detection in RCC. Herein, we performed a multicenter, real-world evaluation of the prognostic value of circulating tumor DNA (ctDNA) in resected RCC. METHODS: This real-world evidence-based multi-institutional study included a cohort of 77 patients with stage I-IV RCC. Longitudinal ctDNA testing was performed on plasma samples (n = 295) using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera, Natera, Inc, Austin, TX). ctDNA results were analyzed, and association with recurrence-free survival was assessed. RESULTS: The patient cohort included 77 patients with stage I-IV RCC (clear cell: 64, non–clear cell: 13). Patients who tested ctDNA-positive during the MRD window experienced worse prognosis and a higher likelihood of recurrence (hazard ratios, 18; P < .0001) compared with their ctDNA-negative counterparts. CONCLUSION: Overall, we demonstrate the utility of ctDNA testing for MRD detection. Future prospective studies in RCC would be needed to validate the utility of ctDNA in informing clinical decision making.