In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer

Momcilovic, Milica; Jones, Anthony E.; Bailey, Sean T.; Waldmann, Christopher M.; Li, Rui; Lee, Jason T.; Abdelhady, Gihad; Gomez, Adrian; Holloway, Travis; Schmid, E.; Stout, David; Fishbein, Michael C.; Stiles, Linsey; Dabir, Deepa V.; Dubinett, Steven M.; Christofk, Heather R.; Shirihai, Orian S.; Koehler, Carla M.; Sadeghi, Saman; Shackelford, David B.

doi:10.1038/s41586-019-1715-0

Cited by 164 publications

(130 citation statements)

References 28 publications

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“…Even when glucose uptake is activated, oxidative metabolism persists in the tumour and may exceed that in adjacent non-malignant tissue. New metabolic-imaging agents have added further evidence of concomitant FDG uptake and oxidative metabolism in mouse models of cancer, and some of these agents may soon be used to assess human cancer 15 .…”

Section: Commentmentioning

confidence: 99%

We need to talk about the Warburg effect

2020

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Section: Commentmentioning

confidence: 99%

We need to talk about the Warburg effect

2020

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“…Because of this metabolic feature, the important diagnostic technique of 18 F-fluorodeoxyglucose positron emission tomography ( 18 FDG-PET) (217) was developed and since then used in the clinic for the diagnosis of malignant diseases. Momcilovic et al (218) have been using 4-[ 18 F] fluorobenzyl-triphenylphosphonium ( 18 FBnTP)-a positively charged tracer-ion that is accumulated on the negatively charged inner membrane of mitochondria-to distinguish squamous cell carcinoma from adenocarcinoma in mice, thus providing the opportunity to target their different dependency on oxidative phosphorylation. 18 FBnTP-PET, together with 18 FDG-PET, provides us with a new tool for in vivo-imaging energy and metabolites fluxes to further widen up our diagnostic horizon in treating different states of developing cancers.…”

Section: Resultsmentioning

confidence: 99%

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

2020

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Since the earliest findings of Otto Warburg, who discovered the first metabolic differences between lactate production of cancer cells and non-malignant tissues in the 1920s, much time has passed. He explained the increased lactate levels with dysfunctional mitochondria and aerobic glycolysis despite adequate oxygenation. Meanwhile, we came to know that mitochondria remain instead functional in cancer cells; hence, metabolic drift, rather than being linked to dysfunctional mitochondria, was found to be an active act of direct response of cancer cells to cell proliferation and survival signals. This metabolic drift begins with the use of sugars and the full oxidative phosphorylation via the mitochondrial respiratory chain to form CO 2 , and it then leads to the formation of lactic acid via partial oxidation. In addition to oncogene-driven metabolic reprogramming, the oncometabolites themselves alter cell signaling and are responsible for differentiation and metastasis of cancer cells. The aberrant metabolism is now considered a major characteristic of cancer within the past 15 years. However, the proliferating anabolic growth of a tumor and its spread to distal sites of the body is not explainable by altered glucose metabolism alone. Since a tumor consists of malignant cells and its tumor microenvironment, it was important for us to understand the bilateral interactions between the primary tumor and its microenvironment and the processes underlying its successful metastasis. We here describe the main metabolic pathways and their implications in tumor progression and metastasis. We also portray that metabolic flexibility determines the fate of the cancer cell and ultimately the patient. This flexibility must be taken into account when deciding on a therapy, since singular cancer therapies only shift the metabolism to a different alternative path and create resistance to the medication used. As with Otto Warburg in his days, we primarily focused on the metabolism of mitochondria when dealing with this scientific question.

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“…Additionally, alterations in mitochondrial abundance have been shown in senescent cells, as has mitochondrial regulation of the SASP [58,59]. Therefore, a plausible alternative to identify senescent cells in vivo is by using a novel metabolic stable-isotope tracer, which localizes to the inner membrane of the mitochondria providing a radioactive signal that can be observed with positron emission tomography (PET) [60]. This approach can be used in conjunction with transgenic mouse models to visualize which cells are prone to senesce with age and age-related diseases and, importantly, to profile their metabolic signatures, such as oxidative phosphorylation.…”

Section: Cell Type Specificity Of Cellular Senescencementioning

confidence: 99%

Insights from In Vivo Studies of Cellular Senescence

Prieto

Graves

Baker

2020

Cells

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Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. While less well understood mechanistically, senescence in vivo is becoming appreciated for its numerous biological implications, both in the context of beneficial processes, such as development, tumor suppression, and wound healing, and in detrimental conditions, where senescent cell accumulation has been shown to contribute to aging and age-related diseases. Importantly, clearance of senescent cells, through either genetic or pharmacological means, has been shown to not only extend the healthspan of prematurely and naturally aged mice but also attenuate pathology in mouse models of chronic disease. These observations have prompted an investigation of how and why senescent cells accumulate with aging and have renewed exploration into the characteristics of cellular senescence in vivo. Here, we highlight our molecular understanding of the dynamics that lead to a cellular arrest and how various effectors may explain the consequences of senescence in tissues. Lastly, we discuss how exploitation of strategies to eliminate senescent cells or their effects may have clinical utility.

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In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer

Cited by 164 publications

References 28 publications

We need to talk about the Warburg effect

We need to talk about the Warburg effect

Shedding New Light on Cancer Metabolism: A Metabolic Tightrope Between Life and Death

Insights from In Vivo Studies of Cellular Senescence

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