Slow TCA flux and ATP production in primary solid tumours but not metastases

Bartman, Caroline; Weilandt, Daniel; Shen, Yihui; Lee, Won Dong; Han, Yujiao; TeSlaa, Tara; Jankowski, Connor S.R.; Samarah, Laith Z; Park, Noel R.; Silva-Diz, Victoria da; Aleksandrova, Maya; Gültekin, Yetiş; Marishta, A.; Wang, Lin; Yang, Lifeng; Roichman, Asael; Bhatt, Vrushank; Lan, Taijin; Hu, Zhixian; Xi, Xing; Lu, Wenyun; Davidson, Shawn M.; Wühr, Martin; Heiden, Matthew G. Vander; Herranz, Daniel; Guo, Jessie Yanxiang; Kang, Yibin; Rabinowitz, Joshua D.

doi:10.1038/s41586-022-05661-6

Cited by 159 publications

(85 citation statements)

References 81 publications

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“…Two key points distinguish this work from prior studies on isotope tracing in human cancers. First, whereas earlier studies in other types of human cancer emphasized substantial TCA cycle labeling from [U-13 C]glucose 15,[50][51][52] , ccRCCs generally have low labeling relative to the adjacent kidney. We provide evidence that this is an intrinsic characteristic of ccRCC.…”

Section: Discussionmentioning

confidence: 92%

“…Evidence from mice indicates that the TCA cycle and oxidative phosphorylation may promote multiple aspects of cancer progression, including metastasis. Quantitative measurement of TCA cycle flux in orthotopic models of breast cancer reported a large increase in flux after metastasis to the lung 52 . In melanoma, the formation and growth of brain metastases in mice is suppressed by inhibiting ETC Complex I 53 .…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial metabolism in primary and metastatic human kidney cancers

Bezwada

DeBerardinis

Lesner

et al. 2023

Preprint

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Most kidney cancers display evidence of metabolic dysfunction1–4but how this relates to cancer progression in humans is unknown. We used a multidisciplinary approach to infuse13C-labeled nutrients during surgical tumour resection in over 70 patients with kidney cancer. Labeling from [U-13C]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 [1,2-13C]acetate and [U-13C]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.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Mitochondrial metabolism in primary and metastatic human kidney cancers

Bezwada

DeBerardinis

Lesner

et al. 2023

Preprint

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show abstract

“…To meet their metabolic needs and maintain malignant proliferation, cancer cells must obtain and effectively utilize essential nutrients from a nutrient-poor environment. Tumor cells thus undergo the transformation of glucose metabolism from oxidative phosphorylation to the glycolytic pathway, which is characterized by high glucose consumption, low ATP synthesis, and high lactic acid production [ 28 ]. This phenomenon was first described by the German physiologist Otto Warburg [ 29 ].…”

Section: Ubiquitination and Deubiquitination Of Metabolic Enzymesmentioning

confidence: 99%

The Ubiquitin–Proteasome System in Tumor Metabolism

Wang

Xiang

Fan

et al. 2023

Cancers

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Metabolic reprogramming, which is considered a hallmark of cancer, can maintain the homeostasis of the tumor environment and promote the proliferation, survival, and metastasis of cancer cells. For instance, increased glucose uptake and high glucose consumption, known as the “Warburg effect,” play an essential part in tumor metabolic reprogramming. In addition, fatty acids are harnessed to satisfy the increased requirement for the phospholipid components of biological membranes and energy. Moreover, the anabolism/catabolism of amino acids, such as glutamine, cystine, and serine, provides nitrogen donors for biosynthesis processes, development of the tumor inflammatory environment, and signal transduction. The ubiquitin–proteasome system (UPS) has been widely reported to be involved in various cellular biological activities. A potential role of UPS in the metabolic regulation of tumor cells has also been reported, but the specific regulatory mechanism has not been elucidated. Here, we review the role of ubiquitination and deubiquitination modification on major metabolic enzymes and important signaling pathways in tumor metabolism to inspire new strategies for the clinical treatment of cancer.

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“…These results are in contrast to our interpretation of lower oxygen levels as indicating increased oxygen consumption. A recent study on tumor tissue metabolism demonstrated that there are significant changes in both production and consumption of ATP in proliferating cells such that the ATP levels were rebalanced without a net change in the overall ATP levels ( Bartman et al, 2023 ). It is possible that such a rebalancing of oxygen consumption, ATP production and biosynthetic processes may occur in the proliferating liver tissue post PHx.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal ultrasound imaging and network modeling in rats reveal sex-dependent suppression of liver regeneration after resection in alcoholic liver disease

Barnhart

Kan²,

Srivastava³

et al. 2023

Front. Physiol.

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Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5–7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats. Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration.

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Slow TCA flux and ATP production in primary solid tumours but not metastases

Cited by 159 publications

References 81 publications

Mitochondrial metabolism in primary and metastatic human kidney cancers

Mitochondrial metabolism in primary and metastatic human kidney cancers

The Ubiquitin–Proteasome System in Tumor Metabolism

Longitudinal ultrasound imaging and network modeling in rats reveal sex-dependent suppression of liver regeneration after resection in alcoholic liver disease

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