Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer
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Cultured cells convert glucose to lactate, and glutamine is the major source of tricarboxylic acid (TCA)-cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells.
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Cancer cells metabolised glutamine differently when cultured as monolayers or spheroids or when transplanted as tumours.
“cancer cells metabolised glutamine differently when they were cultured as monolayers or spheroids [77] or when they were transplanted as tumours [78].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [78]
Cell lines derived from resistant lung tumors become sensitive to glutaminase inhibition in vitro, highlighting that environment can contribute to glutaminase sensitivity.
“Importantly, cell lines derived from resistant lung tumors become sensitive to glutaminase inhibition in vitro, highlighting that environment can be a contributor to glutaminase sensitivity (Davidson et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Davidson et al., 2016
Glutamine tracing studies have demonstrated that in some tumor tissues glutamine contributes minimally to TCA cycle intermediates, and those cancers can be resistant to glutaminase inhibition.
“Glutamine tracing studies have demonstrated that in some tumor tissues, glutamine contributes minimally to TCA cycle intermediates, and those cancers can be resistant to glutaminase inhibition (Davidson et al., 2016; Hensley et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Tardito et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Davidson et al., 2016
Cancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase.
“Cancer tissue-of-origin has served as a successful way to select patients for chemotherapies targeting metabolism for decades, and environment can also influence the efficacy of drugs targeting DHODH, mitochondrial complex I, and glutaminase (Davidson et al., 2016; Gui et al., 2016; Marin-Valencia et al., 2012; Sellers et al., 2015; Sykes et al., 2016; Tardito et al., 2015).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Davidson et al., 2016
Not all KRAS tumors are sensitive to inhibition of glutamine metabolism in vivo.
“Consistently, not all KRAS tumors are sensitive to inhibition of glutamine metabolism in vivo74,75, indicating that a deeper understanding is required of the context in which KRAS-driven cancers would be most sensitive to agents that target this metabolic pathway.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [74]
K-Ras-driven mouse lung tumors preferentially utilize glucose more than glutamine to supply carbon to the TCA cycle via pyruvate carboxylase.
“It has been reported that K-Ras-driven mouse lung tumors preferentially utilize glucose more than glutamine to supply carbon to the TCA cycle via pyruvate carboxylase192.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [192]
PDAC cells utilize macropinocytosis to obtain amino acids through uptake and degradation of albumin and collagen.
“PDAC cells utilize macropinocytosis to obtain amino acids through the uptake and degradation of albumin and collagen230–232”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [231]
Isotope tracing studies in lung and glioblastoma tumors suggest that glutamine is a relatively minor source of TCA cycle carbon in some cancer cells growing in vivo.
“However, isotope tracing studies in both lung and glioblastoma tumors suggest that glutamine is a relatively minor source of TCA cycle carbon in some cancer cells growing in vivo, indicating that environmental context can drive fuel preferences (193, 194).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [193]
Many cancers favor PC-mediated anaplerosis.
“Many cancers favor PC-mediated anaplerosis, although the factors that dictate the choice for pyruvate flux between PC and PDC are little studied.27,29,30”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [30]
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- Authors
- Davidson, S. M., Papagiannakopoulos, T., Olenchock, B. A., Heyman, J. E., Keibler, M. A., Luengo, A., Bauer, M. R., Jha, A. K., O’Brien, J. P., Pierce, K. A., Gui, D. Y., Sullivan, L. B., Wasylenko, T. M., Subbaraj, L., Chin, C. R., Stephanopolous, G., Mott, B. T., Jacks, T., Clish, C. B., & Vander Heiden, M. G.
- Affiliations
- Broad Institute (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Massachusetts Institute of Technology (US)
- National Institutes of Health (US)
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 23
- Issue
- 3
- Pages
- 517-528
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4785096
- OpenAlex
- W2264411128
- Cited by
- 737
- References
- 49
- Citations by year
- 2026: 39 · 2025: 35 · 2024: 54 · 2023: 68 · 2022: 75 · 2021: 106 · 2020: 77 · 2019: 88 · 2018: 59 · 2017: 84 · 2016: 52
- FWCI
- 39.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K08HL119355)
- National Cancer Institute (P30CA1405141, R01CA168653, P30CA014051)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer and biochemical research
- Keywords
- non-small cell lung cancer, cancer metabolism, glucose metabolism, glutamine metabolism, TCA cycle, lactic acid production, tumor microenvironment, glucose oxidation
- MeSH terms
- Animals, Blood Glucose, Carcinoma, Non-Small-Cell Lung, Glucose, Humans, Lung, Lung Neoplasms, Mice, Inbred C57BL, Mice, Nude, Mitochondria, Neoplasm Transplantation, Proto-Oncogene Proteins p21(ras), Pyruvic Acid, Mutation, Missense, Cell Line, Tumor, Mice, 129 Strain, Tumor Microenvironment
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