bims-glucam 2021-10-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021‒10‒17
sixteen papers selected by
Sreeparna Banerjee
Middle East Technical University

SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with immunotherapeutic potential.
SLC1A5 provides glutamine and asparagine necessary for bone development in mice.
Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.
Glutamine and Cholesterol Plasma Levels and Clinical Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Taxanes.
Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.
Autophagy and cancer metabolism-The two-way interplay.
Glutamine restores mitochondrial respiration in bleomycin-injured epithelial cells.
The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity.
LC-MS Based Metabolomics Study of the Effects of EGCG on A549 Cells.
Intracellular metabolic reprogramming mediated by micro-RNAs in differentiating and proliferating cells under non-diseased conditions.
Pyruvate and Glutamine Define the Effects of Cholecystokinin and Ethanol on Mitochondrial Oxidation, Necrosis, and Morphology of Rat Pancreatic Acini.
Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer.
Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors.
Redox Regulation in Cancer Cells during Metastasis.
Metabolic Plasticity and Combinatorial Radiosensitisation Strategies in Human Papillomavirus-Positive Squamous Cell Carcinoma of the Head and Neck Cell Lines.
Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.

EBioMedicine. 2021 Oct 07. pii: S2352-3964(21)00407-2. [Epub ahead of print]72 103614

SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with immunotherapeutic potential.

Jie Xiong, Nan Wang, Hui-Juan Zhong, Bo-Wen Cui, Shu Cheng, Rui Sun, Jia-Yi Chen, Peng-Peng Xu, Gang Cai, Li Wang, Xiao-Jian Sun, Jin-Yan Huang, Wei-Li Zhao.

  BACKGROUND: Metabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment.METHODS: To understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models.
FINDINGS: In NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens.
INTERPRETATION: SLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL.
FUNDING: This study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.

Keywords:  Anti-PD-1 antibody; EAAT3; Glutamine; Metabolomics; Natural-killer T-cell lymphoma; RNA-sequencing; Solute carrier family 1 member 1

DOI:  https://doi.org/10.1016/j.ebiom.2021.103614
Elife. 2021 Oct 14. pii: e71595. [Epub ahead of print]10

SLC1A5 provides glutamine and asparagine necessary for bone development in mice.

Deepika Sharma, Yilin Yu, Leyao Shen, Guo-Fang Zhang, Courtney M Karner.

  Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here we identify SLC1A5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show SLC1A5 acts cell autonomously to regulate protein synthesis and osteoblast differentiation. SLC1A5 provides both glutamine and asparagine which are essential for osteoblast differentiation. Mechanistically, glutamine and to a lesser extent asparagine support amino acid biosynthesis. Thus, osteoblasts depend on Slc1a5 to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.

Keywords:  cell biology; developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.71595
Adv Sci (Weinh). 2021 Oct 10. e2100997

Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.

Xuemei Yao, Wei Li, De Fang, Chuyu Xiao, Xiao Wu, Menghuan Li, Zhong Luo.

  Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the regulation of key ferroptosis markers such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS), therefore imposing potential regulatory roles in ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit ferroptosis for self-preservation such as the upregulation of glycolysis and PPP. Due to the rapid proliferation of tumor cells and the intensified metabolic rate, tumor energy metabolism has become a target for disrupting the redox homeostasis and induce ferroptosis. Based on these emerging insights, regulatory impact of those-tumor specific metabolic aberrations is systematically characterized, such as rewired glucose metabolism and metabolic compensation through glutamine utilization on ferroptosis and analyzed the underlying molecular mechanisms. Additionally, those ferroptosis-based therapeutic strategies are also discussed by exploiting those metabolic vulnerabilities, which may open up new avenues for tumor treatment in a clinical context.

Keywords:  cellular energy metabolism; ferroptosis; glucose; glutamine

DOI:  https://doi.org/10.1002/advs.202100997
Cancers (Basel). 2021 Oct 01. pii: 4960. [Epub ahead of print]13(19):

Glutamine and Cholesterol Plasma Levels and Clinical Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Taxanes.

Mercedes Marín-Aguilera, María V Pereira, Natalia Jiménez, Òscar Reig, Anna Cuartero, Iván Victoria, Caterina Aversa, Laura Ferrer-Mileo, Aleix Prat, Begoña Mellado.

  Altered metabolism is a hallmark of cancer. Malignant cells metabolise glutamine to fulfil their metabolic needs. In prostate cancer, androgen receptor signalling promotes glutamine metabolism, which is also involved in cholesterol homeostasis. We aimed to determine whether the plasma glutamine levels correlate with the blood lipid profile, clinical characteristics and outcomes in patients with metastatic castration resistance prostate cancer (mCRPC) undergoing taxanes. We retrospectively assessed the glutamine and glutamate levels in plasma samples by a bioluminescent assay. Pre-treatment glutamine, glutamate, cholesterol and triglycerides levels were correlated with patients' clinical characteristics, taxanes response and clinical outcomes. Seventy-five patients with mCRPC treated with taxanes were included. The plasma glutamine levels were significantly higher in patients that received abiraterone or enzalutamide prior to taxanes (p = 0.003). Besides, patients with low glutamine levels were more likely to present a PSA response to taxanes (p = 0.048). Higher glutamine levels were significantly correlated with shorter biochemical/clinical progression-free survival (PSA/RX-PFS) (median 2.5 vs. 4.2 months; p = 0.048) and overall survival (OS) (median 12.6 vs. 20.3; p = 0.008). High cholesterol levels independently predicted early PSA/RX-PFS (p = 0.034). High glutamine and cholesterol in the plasma from patients with mCRPC were associated with adverse clinical outcomes, supporting the relevance of further research on metabolism in prostate cancer progression.

Keywords:  biomarkers; glutamine; liquid biopsy; metabolism; prostate cancer; taxanes

DOI:  https://doi.org/10.3390/cancers13194960
Nat Metab. 2021 Oct 14.

Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.

Johanna Merlin, Stoyan Ivanov, Adélie Dumont, Alexey Sergushichev, Julie Gall, Marion Stunault, Marion Ayrault, Nathalie Vaillant, Alexia Castiglione, Amanda Swain, Francois Orange, Alexandre Gallerand, Thierry Berton, Jean-Charles Martin, Stefania Carobbio, Justine Masson, Inna Gaisler-Salomon, Pierre Maechler, Stephen Rayport, Judith C Sluimer, Erik A L Biessen, Rodolphe R Guinamard, Emmanuel L Gautier, Edward B Thorp, Maxim N Artyomov, Laurent Yvan-Charvet.

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.

DOI: https://doi.org/10.1038/s42255-021-00471-y
IUBMB Life. 2021 Oct 15.

Autophagy and cancer metabolism-The two-way interplay.

Reui-Liang Yan, Ruey-Hwa Chen.

  Autophagy is an intracellular catabolic process that degrades cytoplasmic components for recycling in response to stressed conditions, such as nutrient deprivation. Dysregulation of autophagy is associated with various diseases, including cancer. Although autophagy plays dichotomous and context-dependent roles in cancer, evidence has emerged that cancer cells exploit autophagy for metabolic adaptation. Autophagy is upregulated in many cancer types through tumor cell-intrinsic proliferation demands and the hypoxic and nutrient-limited tumor microenvironment (TME). Autophagy-induced breakdown products then fuel into various metabolic pathways to supply tumor cells with energy and building blocks for biosynthesis and survival. This bidirectional regulation between autophagy and tumor constitutes a vicious cycle to potentiate tumor growth and therapy resistance. In addition, the pro-tumor functions of autophagy are expanded to host, including cells in TME and distant organs. Thus, inhibition of autophagy or autophagy-mediated metabolic reprogramming may be a promising strategy for anticancer therapy. Better understanding the metabolic rewiring mechanisms of autophagy for its pro-tumor effects will provide insights into patient treatment.

Keywords:  anticancer therapy; autophagy; cancer; metabolism; tumor microenvironment

DOI:  https://doi.org/10.1002/iub.2569
Free Radic Biol Med. 2021 Oct 08. pii: S0891-5849(21)00754-1. [Epub ahead of print]

Glutamine restores mitochondrial respiration in bleomycin-injured epithelial cells.

Hoora Shaghaghi, Rachel Para, Cara Tran, Jesse Roman, Yemaiza Ojeda-Lassalle, Jianxin Sun, Freddy Romero, Ross Summer.

  Whether from known or unknown causes, loss of epithelial repair plays a central role in the pathogenesis of pulmonary fibrosis. Recently, diminished mitochondrial function has been implicated as a factor contributing to the loss of epithelial repair but the mechanisms mediating these changes have not been defined. Here, we investigated the factors contributing to mitochondrial respiratory dysfunction after bleomycin, a widely accepted agent for modeling pulmonary fibrosis in mice and in vitro systems. In agreement with previous reports, we found that mitochondrial respiration was decreased in lung epithelial cells exposed to bleomycin, but we also observed that responses differed depending on the type of metabolic fuel available to cells. For example, we found that mitochondrial respiration was dramatically reduced when glucose served as the primary fuel. Moreover, this associated with a marked decrease in glucose uptake, expression of glucose uptake transport 1 and capacity to augment glycolysis to either glucose or oligomycin. Conversely, mitochondrial respiration was largely preserved if glutamine was present in culture medium. The addition of glutamine also lead to increased intracellular metabolite levels, including multiple TCA cycle intermediates and the glycolytic intermediate lactate, and was associated with reduced DNA damage and cell death to bleomycin. In summary, our findings indicate that glutamine, rather than glucose, supports mitochondrial respiration and metabolite production in injured lung epithelium, and suggest that this shift away from glucose utilization serves to protect the lung epithelium from bleomycin injury.

Keywords:  13C fluxomics; 13CNMR; DNA damage; Epithelium; Glutamine; LC-MS/MS; Metabolic reprogramming; Mitochondria; Targeted metabolomics

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.10.006
Arch Immunol Ther Exp (Warsz). 2021 Oct 12. 69(1): 29

The Role of Non-essential Amino Acids in T Cell Function and Anti-tumour Immunity.

Helen Carrasco Hope, Robert J Salmond.

  T cell activation, differentiation and proliferation is dependent upon and intrinsically linked to a capacity to modulate and adapt cellular metabolism. Antigen-induced activation stimulates a transcriptional programme that results in metabolic reprogramming, enabling T cells to fuel anabolic metabolic pathways and provide the nutrients to sustain proliferation and effector responses. Amino acids are key nutrients for T cells and have essential roles as building blocks for protein synthesis as well as in numerous metabolic pathways. In this review, we discuss the roles for uptake and biosynthesis of non-essential amino acids in T cell metabolism, activation and effector function. Furthermore, we highlight the effects of amino acid metabolism and depletion by cancer cells on T cell anti-tumour function and discuss approaches to modulate and improve T cell metabolism for improved anti-tumour function in these nutrient-depleted microenvironments.

Keywords:  Immunotherapy; Metabolism; Non-essential amino acid; T cell; Tumour microenvironment

DOI:  https://doi.org/10.1007/s00005-021-00633-6
Front Pharmacol. 2021 ;12 732716

LC-MS Based Metabolomics Study of the Effects of EGCG on A549 Cells.

Tingyu Pan, Di Han, Yong Xu, Wenpan Peng, Le Bai, Xianmei Zhou, Hailang He.

  (-)-Epigallocatechin-3-gallate (EGCG) is the main bioactive catechin in green tea. The antitumor activity of EGCG has been confirmed in various types of cancer, including lung cancer. However, the precise underlying mechanisms are still largely unclear. In the present study, we investigated the metabolite changes in A549 cells induced by EGCG in vitro utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. The result revealed 33 differentially expressed metabolites between untreated and 80 μM EGCG-treated A549 cells. The altered metabolites were involved in the metabolism of glucose, amino acid, nucleotide, glutathione, and vitamin. Two markedly altered pathways, including glycine, serine and threonine metabolism and alanine, aspartate and glutamate metabolism, were identified by MetaboAnalyst 5.0 metabolic pathway analysis. These results may provide potential clues for the intramolecular mechanisms of EGCG's effect on A549 cells. Our study may contribute to future molecular mechanistic studies of EGCG and the therapeutic application of EGCG in cancer management.

Keywords:  A549 cells; EGCG; arginine and proline metabolism; glutamate metabolism; histidine metabolism; metabolomics

DOI:  https://doi.org/10.3389/fphar.2021.732716
Mol Biol Rep. 2021 Oct 13.

Intracellular metabolic reprogramming mediated by micro-RNAs in differentiating and proliferating cells under non-diseased conditions.

Varsha Singh.

  Intracellular metabolic reprogramming is a critical process the cells carry out to increase biomass, energy fulfillment and genome replication. Cells reprogram their demands from internal catabolic or anabolic activities in coordination with multiple genes and microRNAs which further control the critical processes of differentiation and proliferation. The microRNAs reprogram the metabolism involving mitochondria, the nucleus and the biochemical processes utilizing glucose, amino acids, lipids, and nucleic acids resulting in ATP production. The processes of glycolysis, tricarboxylic acid cycle, or oxidative phosphorylation are also mediated by micro-RNAs maintaining cells and organs in a non-diseased state. Several reports have shown practical applications of metabolic reprogramming for clinical utility to assess various diseases, mostly studying cancer and immune-related disorders. Cells under diseased conditions utilize glycolysis for abnormal growth or proliferation, respectively, affecting mitochondrial paucity and biogenesis. Similar metabolic processes also affect gene expressions and transcriptional regulation for carrying out biochemical reactions. Metabolic reprogramming is equally vital for regulating cell environment to maintain organs and tissues in non-diseased states. This review offers in depth insights and analysis of how miRNAs regulate metabolic reprogramming in four major types of cells undergoing differentiation and proliferation, i.e., immune cells, neuronal cells, skeletal satellite cells, and cardiomyocytes under a non-diseased state. Further, the work systematically summarizes and elaborates regulation of genetic switches by microRNAs through predominantly through cellular reprogramming and metabolic processes for the first time. The observations will lead to a better understanding of disease initiation during the differentiation and proliferation stages of cells, as well as fresh approaches to studying clinical onset of linked metabolic diseases targeting metabolic processes.

Keywords:  Cell differentiation; Cell proliferation; Gene regulation; Metabolic reprogramming; MicroRNAs; Signal transduction

DOI:  https://doi.org/10.1007/s11033-021-06769-0
Pancreas. 2021 Aug 01. 50(7): 972-981

Pyruvate and Glutamine Define the Effects of Cholecystokinin and Ethanol on Mitochondrial Oxidation, Necrosis, and Morphology of Rat Pancreatic Acini.

Bohdan O Manko, Olha O Bilonoha, Dariia M Voloshyn, Anastasiia M Zub, Iryna I Ivasechko, Volodymyr V Manko.

OBJECTIVES: The objective of this study was to test whether pyruvate and glutamine affect the ethanol and cholecystokinin (CCK) effects on the mitochondrial function, viability, and morphology of rat pancreatic acini.METHODS: Respiration was measured with Clark oxygen electrode. Mitochondrial membrane potential, reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H), cell morphology, and viability were studied with fluorescence microscopy.
RESULTS: In vitro, CCK (0.1 nM) caused pyruvate-dependent stimulation of basal and uncoupled respiration, and the effects were abolished by ethanol (20 mM). The combination of ethanol with CCK (2 hours) caused necrosis of approximately 40% acinar cells in medium with glucose, but not with pyruvate and/or glutamine. Cholecystokinin (10 nM) or ethanol with 0.1 nM CCK caused plasma membrane blebbing not related to apoptosis only when both glutamine and pyruvate were present. Glutamine, but not pyruvate, decreased NAD(P)H level and prevented the effects of ethanol with CCK on mitochondrial membrane potential and NAD(P)H, but, in combination with CCK and ethanol, decreased the uncoupled respiration. In vivo, the combination of ethanol (4 g/kg) and CCK (20 pmol/kg) suppressed basal and uncoupled respiration and caused acinar cell blebbing, but not necrosis.
CONCLUSIONS: The lack of sufficient substrate supply in vitro makes pancreatic acinar cells susceptible to necrosis caused by ethanol and CCK in clinically relevant concentrations.

DOI: https://doi.org/10.1097/MPA.0000000000001864
Cancers (Basel). 2021 Sep 26. pii: 4808. [Epub ahead of print]13(19):

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer.

Shaimaa Hussein, Pooja Khanna, Neha Yunus, Michael L Gatza.

  Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.

Keywords:  breast cancer; endocrine resistance; estrogen receptor; luminal; metabolic reprogramming; nuclear receptors

DOI:  https://doi.org/10.3390/cancers13194808
Front Oncol. 2021 ;11 700629

Mechanisms Governing Metabolic Heterogeneity in Breast Cancer and Other Tumors.

Sayani Patra, Naveed Elahi, Aaron Armorer, Swathi Arunachalam, Joshua Omala, Iman Hamid, Anthony W Ashton, David Joyce, Xuanmao Jiao, Richard G Pestell.

  Reprogramming of metabolic priorities promotes tumor progression. Our understanding of the Warburg effect, based on studies of cultured cancer cells, has evolved to a more complex understanding of tumor metabolism within an ecosystem that provides and catabolizes diverse nutrients provided by the local tumor microenvironment. Recent studies have illustrated that heterogeneous metabolic changes occur at the level of tumor type, tumor subtype, within the tumor itself, and within the tumor microenvironment. Thus, altered metabolism occurs in cancer cells and in the tumor microenvironment (fibroblasts, immune cells and fat cells). Herein we describe how these growth advantages are obtained through either "convergent" genetic changes, in which common metabolic properties are induced as a final common pathway induced by diverse oncogene factors, or "divergent" genetic changes, in which distinct factors lead to subtype-selective phenotypes and thereby tumor heterogeneity. Metabolic heterogeneity allows subtyping of cancers and further metabolic heterogeneity occurs within the same tumor mass thought of as "microenvironmental metabolic nesting". Furthermore, recent findings show that mutations of metabolic genes arise in the majority of tumors providing an opportunity for the development of more robust metabolic models of an individual patient's tumor. The focus of this review is on the mechanisms governing this metabolic heterogeneity in breast cancer.

Keywords:  Cyclin D1; PPAR-γ; Warburg effect; aerobic glycolysis; breast cancer; epigenetics; metabolism; reverse Warburg effect

DOI:  https://doi.org/10.3389/fonc.2021.700629
Cancer Discov. 2021 Oct 14.

Redox Regulation in Cancer Cells during Metastasis.

Alpaslan Tasdogan, Jessalyn M Ubellacker, Sean J Morrison.

Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells. SIGNIFICANCE: Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0558
Cancers (Basel). 2021 Sep 28. pii: 4836. [Epub ahead of print]13(19):

Metabolic Plasticity and Combinatorial Radiosensitisation Strategies in Human Papillomavirus-Positive Squamous Cell Carcinoma of the Head and Neck Cell Lines.

Mark D Wilkie, Emad A Anaam, Andrew S Lau, Carlos P Rubbi, Nikolina Vlatkovic, Terence M Jones, Mark T Boyd.

  BACKGROUND: A major objective in the management of human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) is to reduce long-term functional ramifications while maintaining oncological outcomes. This study examined the metabolic profile of HPV-positive SCCHN and the potential role of anti-metabolic therapeutics to achieve radiosensitisation as a potential means to de-escalate radiation therapy.METHODS: Three established HPV-positive SCCHN cell lines were studied (UM-SCC-104, UPCI:SCC154, and VU-SCC-147), together with a typical TP53 mutant HPV-negative SCCHN cell line (UM-SCC-81B) for comparison. Metabolic profiling was performed using extracellular flux analysis during specifically designed mitochondrial and glycolytic stress tests. Sensitivity to ionising radiation (IR) was evaluated using clonogenic assays following no treatment, or treatment with: 25 mM 2-deoxy-D-glucose (glycolytic inhibitor) alone; 20 mM metformin (electron transport chain inhibitor) alone; or 25 mM 2-deoxy-D-glucose and 20 mM metformin combined. Expression levels of p53 and reporters of p53 function (MDM2, p53, Phospho-p53 [Ser15], TIGAR and p21 [CDKN1A]) were examined by western blotting.
RESULTS: HPV-positive SCCHN cell lines exhibited a diverse metabolic phenotype, displaying robust mitochondrial and glycolytic reserve capacities. This metabolic profile, in turn, correlated with IR response following administration of anti-metabolic agents, in that both 2-deoxy-D-glucose and metformin were required to significantly potentiate the effects of IR in these cell lines.
CONCLUSIONS: In contrast to our recently published data on HPV-negative SCCHN cells, which display relative glycolytic dependence, HPV-positive SCCHN cells can only be sensitised to IR using a complex anti-metabolic approach targeting both mitochondrial respiration and glycolysis, reflecting their metabolically diverse phenotype. Notionally, this may provide an attractive platform for treatment de-intensification in the clinical setting by facilitating IR dose reduction to minimise the impact of treatment on long-term function.

Keywords:  cancer; glycolysis; head and neck cancer; human papillomavirus; metabolism; oxidative phosphorylation; p53

DOI:  https://doi.org/10.3390/cancers13194836
Cancer Cell. 2021 Oct 12. pii: S1535-6108(21)00497-9. [Epub ahead of print]

Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.

Joseph M Chan, Álvaro Quintanal-Villalonga, Vianne Ran Gao, Yubin Xie, Viola Allaj, Ojasvi Chaudhary, Ignas Masilionis, Jacklynn Egger, Andrew Chow, Thomas Walle, Marissa Mattar, Dig V K Yarlagadda, James L Wang, Fathema Uddin, Michael Offin, Metamia Ciampricotti, Besnik Qeriqi, Amber Bahr, Elisa de Stanchina, Umesh K Bhanot, W Victoria Lai, Matthew J Bott, David R Jones, Arvin Ruiz, Marina K Baine, Yanyun Li, Natasha Rekhtman, John T Poirier, Tal Nawy, Triparna Sen, Linas Mazutis, Travis J Hollmann, Dana Pe'er, Charles M Rudin.

  Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.

Keywords:  PLCG2; SCLC; metastasis; myeloid; scRNA-seq; single cell; tumor atlas

DOI:  https://doi.org/10.1016/j.ccell.2021.09.008