Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption ...by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
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•Physiologic disruption of circadian rhythms accelerates lung cancer•Genetic loss of Per2 or Bmal1 promotes lung tumorigenesis•Cell-autonomous loss of circadian genes enhances transformation and growth•Circadian rhythm disruption leads to increased c-Myc levels and metabolic reprogramming
Papagiannakopoulos et al. demonstrate that both physiologic and genetic circadian rhythm disruption accelerates lung tumorigenesis in mice, pointing to a tumor cell-autonomous, tumor-suppressive role of the circadian machinery. Mechanistically, circadian rhythm disruption leads to increased c-Myc levels, enhanced proliferation, and metabolic reprogramming.
The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice ...with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.
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•PKM2 is not required by all tumor cells•The need for pyruvate kinase is most apparent in nonproliferating tumor cells•PKM2 expression is variable in human cancers•Recurrent point mutations disrupting pyruvate kinase are found in human cancers
Loss of PKM2, an isoform of pyruvate kinase that was previously associated with a number of cancers, is in fact found to exacerbate tumor growth. Proliferating tumor cells do not seem to require M1 isoform either, suggesting that it is the inactive state of PKM2 that these cells seem to prefer.
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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•Metabolic phenotyping of tumors can identify essential metabolic pathways•Kras-driven lung tumors require pyruvate carboxylase and pyruvate dehydrogenase•Kras-driven lung tumors are less dependent on glutaminase than cultured cells•Tissue environment is an important determinant of tumor metabolic phenotypes
Davidson et al. find that lung cancer cells in culture use nutrients differently than lung tumors, especially regarding glutamine metabolism. This difference in metabolic phenotype reflects how the tumor environment determines nutrient dependency and highlights the importance of studying cancer metabolism in a physiological context.
Lysosomes (or lytic bodies) were so named because they contain high levels of hydrolytic enzymes. Lysosome function and dysfunction have been found to play important roles in human disease, including ...cancer; however, the ways in which lysosomes contribute to tumorigenesis and cancer progression are still being uncovered. Beyond serving as a cellular recycling center, recent evidence suggests that the lysosome is involved in energy homeostasis, generating building blocks for cell growth, mitogenic signaling, priming tissues for angiogenesis and metastasis formation, and activating transcriptional programs. This review examines emerging knowledge of how lysosomal processes contribute to the hallmarks of cancer and highlights vulnerabilities that might be exploited for cancer therapy.
Metformin use is associated with reduced cancer mortality, but how metformin impacts cancer outcomes is controversial. Although metformin can act on cells autonomously to inhibit tumor growth, the ...doses of metformin that inhibit proliferation in tissue culture are much higher than what has been described in vivo. Here, we show that the environment drastically alters sensitivity to metformin and other complex I inhibitors. We find that complex I supports proliferation by regenerating nicotinamide adenine dinucleotide (NAD)+, and metformin’s anti-proliferative effect is due to loss of NAD+/NADH homeostasis and inhibition of aspartate biosynthesis. However, complex I is only one of many inputs that determines the cellular NAD+/NADH ratio, and dependency on complex I is dictated by the activity of other pathways that affect NAD+ regeneration and aspartate levels. This suggests that cancer drug sensitivity and resistance are not intrinsic properties of cancer cells, and demonstrates that the environment can dictate sensitivity to therapies that impact cell metabolism.
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•Metformin inhibits cell proliferation by decreasing the intracellular NAD+/NADH ratio•Metformin treatment in vivo leads to decreased tumor NAD+ and aspartate•The environment dictates cellular dependence on mitochondrial complex I•Drug sensitivity and resistance can be influenced by the environment
Metformin use is associated with reduced cancer mortality. Gui et al. show that metformin reduces cell proliferation by decreasing the NAD+/NADH ratio and inhibiting aspartate production. Additionally, they show that the metabolic environment influences sensitivity to metformin, suggesting that drug sensitivity or resistance is not necessarily an intrinsic property of cancer cells.
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. ...Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
The study by Benjamin and colleagues demonstrates that mutant YAP expression is sufficient to enhance tumor cell dissemination in zebrafish and mice. Moreover, the integration of approaches in ...biology and engineering taken here provides an important framework to link physical, physiological, and molecular properties of disseminated tumor cells (DTC). Similar integrated approaches will pave the way for future studies to generate global cancer cell dissemination maps and provide further insight into the prognostic value of DTCs for metastatic organotropisms.
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Rewiring of metabolic pathways is a hallmark of tumorigenesis as cancer cells acquire novel nutrient dependencies to support oncogenic growth. A major genetic subtype of lung adenocarcinoma with ...KEAP1/NRF2 mutations, which activates the endogenous oxidative stress response, undergoes significant metabolic rewiring to support enhanced antioxidant production. We demonstrate that cancers with high antioxidant capacity exhibit a general dependency on exogenous non-essential amino acids (NEAAs) that is driven by the Nrf2-dependent secretion of glutamate through system xc− (XCT), which limits intracellular glutamate pools that are required for NEAA synthesis. This dependency can be therapeutically targeted by dietary restriction or enzymatic depletion of individual NEAAs. Importantly, limiting endogenous glutamate levels by glutaminase inhibition can sensitize tumors without alterations in the Keap1/Nrf2 pathway to dietary restriction of NEAAs. Our findings identify a metabolic strategy to therapeutically target cancers with genetic or pharmacologic activation of the Nrf2 antioxidant response pathway by restricting exogenous sources of NEAAs.
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•Keap1 mutations drive non-essential amino acid (NEAA) dependency in cancer•Intracellular glutamate levels dictate cellular ability to survive NEAA deprivation•Restriction of NEAA can suppress Keap1 mutant tumor growth in vivo•Limiting glutamate by glutaminase inhibition enhances response to NEAA deprivation
LeBoeuf et al. describe a general mechanism through which cancer cells depend on non-essential amino acids. Tumor cells with intrinsically low intracellular glutamate require amino acids to be supplied from the extracellular environment. By reducing the amount of circulating amino acids, the authors reduce tumor growth in vivo.
Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support ...the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo.
Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, ...Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.
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