bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022‒08‒28
thirteen papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. Regulation of tumor metabolism by post translational modifications on metabolic enzymes.
  2. Phosphomimetic Dicer S1016E triggers a switch to glutamine metabolism in gemcitabine-resistant pancreatic cancer.
  3. Glutamine metabolism mediates sensitivity to respiratory complex II inhibition in acute myeloid leukemia.
  4. HSF1 Stimulates Glutamine Transport by Super-Enhancer-Driven lncRNA LINC00857 in Colorectal Cancer.
  5. Artificial Diets Based on Selective Amino Acid Restriction versus Capecitabine in Mice with Metastatic Colon Cancer.
  6. Glutamine uptake and catabolism is required for myofibroblast formation and persistence.
  7. Glycosylation defects, offset by PEPCK-M, drive entosis in breast carcinoma cells.
  8. MicroRNAs as Regulators of Cancer Cell Energy Metabolism.
  9. Nanomedicines Targeting Metabolism in the Tumor Microenvironment.
  10. miR-23b-3p Modulating Cytoprotective Autophagy and Glutamine Addiction in Sorafenib Resistant HepG2, a Hepatocellular Carcinoma Cell Line.
  11. Commonalities in Metabolic Reprogramming between Tobacco Use and Oral Cancer.
  12. Metabolic rewiring directs melanoma immunology.
  13. Metastatic triple negative breast cancer adapts its metabolism to destination tissues while retaining key metabolic signatures.
  1. Cancer Gene Ther. 2022 Aug 23.
    Regulation of tumor metabolism by post translational modifications on metabolic enzymes.
    Abhisha Sawant Dessai, Poonam Kalhotra, Aaron T Novickis, Subhamoy Dasgupta.
      Metabolic reprogramming is a hallmark of cancer development, progression, and metastasis. Several metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, lipid metabolism, and glutamine catabolism are frequently altered to support cancer growth. Importantly, the activity of the rate-limiting metabolic enzymes in these pathways are specifically modulated in cancer cells. This is achieved by transcriptional, translational, and post translational regulations that enhance the expression, activity, stability, and substrate sensitivity of the rate-limiting enzymes. These mechanisms allow the enzymes to retain increased activity supporting the metabolic needs of rapidly growing tumors, sustain their survival in the hostile tumor microenvironments and in the metastatic lesions. In this review, we primarily focused on the post translational modifications of the rate-limiting enzymes in the glucose and glutamine metabolism, TCA cycle, and fatty acid metabolism promoting tumor progression and metastasis.
    DOI:  https://doi.org/10.1038/s41417-022-00521-x
  2. Mol Metab. 2022 Aug 19. pii: S2212-8778(22)00145-4. [Epub ahead of print] 101576
    Phosphomimetic Dicer S1016E triggers a switch to glutamine metabolism in gemcitabine-resistant pancreatic cancer.
    Ji Min Park, Jei-Ming Peng, Yu-Shiuan Shen, Chia-Ying Lin, Tung-Wei Hsu, Yen-Hao Su, Hsin-An Chen, Charupong Saengboonmee, Jung-Su Chang, Ching-Feng Chiu, Yan-Shen Shan.
      OBJECTIVE: Dicer is an enzyme that processes microRNAs (miRNAs) precursors into mature miRNAs, which have been implicated in various aspects of cancer progressions, such as clinical aggressiveness, prognosis, and survival outcomes. We previously showed that high expression of Dicer is associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC); thus, in this study, we aimed to focus on how Dicer is involved in GEM resistance in PDAC, including cancer prognosis, cell proliferation, and metabolic regulation.METHODS: We generated stable shRNA knockdown of Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells and explored cell viability by MTT and clonogenicity assays. Metabolomic profiling was employed to investigate metabolic changes between parental cells, PANC-1, and PANC-1 GR cells, and further implied to compare their sensitivity to the glutaminase inhibitor, CB839, and GEM treatments. To identify putative phosphorylation site involves with Dicer and its effects on GEM resistance in PDAC cells, we further generated phosphomimetic or phosphomutant Dicer at S1016 site and examined the changes in drug sensitivity, metabolic alteration, and miRNA regulation.
    RESULTS: We observed that high Dicer levels in pancreatic ductal adenocarcinoma cells were positively correlated with advanced pancreatic cancer and acquired resistance to GEM. Metabolomic analysis indicated that PANC-1 GR cells rapidly utilised glutamine as their major fuel and increased levels of glutaminase (GLS): glutamine synthetase (GLUL) ratio which is related to high Dicer expression. In addition, we found that phosphomimetic Dicer S1016E but not phosphomutant Dicer S1016A facilitated miRNA maturation, causing an imbalance in GLS and GLUL and resulting in an increased response to GLS inhibitors.
    CONCLUSION: Our results suggest that phosphorylation of Dicer on site S1016 affects miRNA biogenesis and glutamine metabolism in GEM-resistant pancreatic cancer.
    Keywords:  Dicer phosphorylation; Gemcitabine resistance; Glutamine metabolism; Pancreatic ductal adenocarcinoma; miRNA biogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2022.101576
  3. Mol Cancer Res. 2022 Aug 22. pii: MCR-21-1032. [Epub ahead of print]
    Glutamine metabolism mediates sensitivity to respiratory complex II inhibition in acute myeloid leukemia.
    Alessia Roma, Matthew Tcheng, Nawaz Ahmed, Sarah Walker, Preethi Jayanth, Mark D Minden, Kristin Hope, Praveen P Nekkar Rao, Jessica Luc, Andrew C Doxey, Julie A Reisz, Rachel Culp-Hill, Angelo D'Alessandro, Paul A Spagnuolo.
      Acute myeloid leukemia (AML) is a hematological malignancy metabolically dependent on oxidative phosphorylation and mitochondrial electron transport chain (ETC) activity. AML cells are distinct from their normal hematopoietic counterparts by this metabolic reprogramming, which presents targets for new selective therapies. Here, metabolic changes in AML cells after ETC impairment are investigated. Genetic knockdown of the ETC complex II (CII) chaperone protein SDHAF1 (succinate dehydrogenase assembly factor 1) suppressed CII activity and delayed AML cell growth in vitro and in vivo. As a result, a novel small molecule that directly binds to the ubiquinone binding site of CII and inhibits its activity was identified. Pharmacological inhibition of CII induced selective cell death in AML cells while sparing normal hematopoietic progenitors. Through stable isotope tracing, results show that genetic or pharmacological inhibition of CII truncates the tricarboxylic acid cycle (TCA) and leads to anaplerotic glutamine metabolism to reestablish the truncated cycle. The inhibition of CII showed divergent fates of AML cells since they lacked the metabolic plasticity to adequately utilize glutamine metabolism, resulting in preferential depletion of key metabolites in the TCA cycle and death; normal cells were unaffected. These findings provide insight into the metabolic mechanisms that underlie AML's selective inhibition of CII. Implications: This work highlights the effects of direct CII inhibition in mediating selective AML cell death and provides insights into glutamine anaplerosis as a metabolic adaptation that can be therapeutically targeted.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-1032
  4. Cancers (Basel). 2022 Aug 09. pii: 3855. [Epub ahead of print]14(16):
    HSF1 Stimulates Glutamine Transport by Super-Enhancer-Driven lncRNA LINC00857 in Colorectal Cancer.
    Qi Shen, Rui Wang, Xinling Liu, Ping Song, Mingzhu Zheng, Xiaomin Ren, Jingang Ma, Zhong Lu, Jiaqiu Li.
      Super enhancers are critical for the gene transcription responsible for cell fate by interacting with transcription factors. However, the relevance of HSF1 to super enhancers in tumors remains obscure. We profiled H3K27ac enrichment by chromatin immunoprecipitation sequencing. HSF1-mediated lncRNAs were identified by lncRNA microarray. The characteristics of LINC00857 were explored by in vitro and in vivo assays. The mechanism was studied via chromatin immunoprecipitation, RNA immunoprecipitation, and HSF1/ANXA11 knockout mice. We found that super enhancers occupied multiple gene loci in colorectal cancer. We screened out an HSF1-mediated super enhancer, lncRNA-LINC00857, which exerts its characteristics in promoting cell growth via regulating glutamine metabolism. Notably, HSF1 could stimulate the super-enhancer activity of LINC00857 by the enrichment of acetyltransferase P300 to its gene loci, contributing to LINC00857 transcription. In turn, nuclear LINC00857 cooperated with HSF1 to promote ANXA11 transcription, which modulated SLC1A5/ASCT2 protein expression by binding competitively to miR-122-5p. The knockout of ANXA11 attenuated colorectal cancer formation in vivo. Collectively, we shed light on a closely cooperative machinery between HSF1 and super enhancers. HSF1 could stimulate acetyltransferase P300-mediated super-enhancer activity to facilitate LINC00857 expression, contributing to SLC1A5-mediated glutamine transport. Targeting the HSF1/LINC00857/ANXA11 axis may provide a valuable therapeutic strategy against colorectal cancer.
    Keywords:  HSF1; LINC00857; colorectal cancer; glutamine metabolism; super enhancer
    DOI:  https://doi.org/10.3390/cancers14163855
  5. Nutrients. 2022 Aug 17. pii: 3378. [Epub ahead of print]14(16):
    Artificial Diets Based on Selective Amino Acid Restriction versus Capecitabine in Mice with Metastatic Colon Cancer.
    Julio José Jiménez-Alonso, Emilio Guillén-Mancina, José Manuel Calderón-Montaño, Víctor Jiménez-González, Patricia Díaz-Ortega, Estefanía Burgos-Morón, Miguel López-Lázaro.
      New therapies are needed to improve the low survival rates of patients with metastatic colon cancer. Evidence suggests that amino acid (AA) restriction can be used to target the altered metabolism of cancer cells. In this work, we evaluated the therapeutic potential of selective AA restriction in colon cancer. After observing anticancer activity in vitro, we prepared several artificial diets and evaluated their anticancer activity in two challenging animal models of metastatic colon cancer. These models were established by injecting CT26.WT murine colon cancer cells in the peritoneum (peritoneal dissemination) or in the tail vein (pulmonary metastases) of immunocompetent BALB/cAnNRj mice. Capecitabine, which is a first-line treatment for patients with metastatic colon cancer, was also evaluated in these models. Mice fed diet TC1 (a diet lacking 10 AAs) and diet TC5 (a diet with 6% casein, 5% glutamine, and 2.5% leucine) lived longer than untreated mice in both models; several mice survived the treatment. Diet TC5 was better than several cycles of capecitabine in both cancer models. Cysteine supplementation blocked the activity of diets TC1 and TC5, but cysteine restriction was not sufficient for activity. Our results indicated that artificial diets based on selective AA restriction have therapeutic potential for colon cancer.
    Keywords:  amino acids; anticancer activity; cancer metabolism; colorectal cancer; cysteine; glutamine; leucine; metastasis; selective amino acid restriction therapy
    DOI:  https://doi.org/10.3390/nu14163378
  6. J Mol Cell Cardiol. 2022 Aug 18. pii: S0022-2828(22)00158-4. [Epub ahead of print]172 78-89
    Glutamine uptake and catabolism is required for myofibroblast formation and persistence.
    Andrew A Gibb, Anh T Huynh, Ryan B Gaspar, Tori L Ploesch, Alyssa A Lombardi, Pawel K Lorkiewicz, Michael P Lazaropoulos, Ken Bedi, Zolt Arany, Kenneth B Margulies, Bradford G Hill, John W Elrod.
      BACKGROUND: Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g., collagens). Myofibroblast persistence in chronic diseases, such as HF, leads to progressive cardiac dysfunction and maladaptive remodeling. We recently reported that an increase in αKG (alpha-ketoglutarate) bioavailability, which contributes to enhanced αKG-dependent lysine demethylase activity and chromatin remodeling, is required for myofibroblast formation. Therefore, we aimed to determine the substrates and metabolic pathways contributing to αKG biosynthesis and their requirement for myofibroblast formation.METHODS: Stable isotope metabolomics identified glutaminolysis as a key metabolic pathway required for αKG biosynthesis and myofibroblast formation, therefore we tested the effects of pharmacologic inhibition (CB-839) or genetic deletion of glutaminase (Gls1-/-) on myofibroblast formation in both murine and human cardiac fibroblasts. We employed immunofluorescence staining, functional gel contraction, western blotting, and bioenergetic assays to determine the myofibroblast phenotype.
    RESULTS: Carbon tracing indicated enhanced glutaminolysis mediating increased αKG abundance. Pharmacological and genetic inhibition of glutaminolysis prevented myofibroblast formation indicated by a reduction in αSMA+ cells, collagen gel contraction, collagen abundance, and the bioenergetic response. Inhibition of glutaminolysis also prevented TGFβ-mediated histone demethylation and supplementation with cell-permeable αKG rescued the myofibroblast phenotype. Importantly, inhibition of glutaminolysis was sufficient to prevent myofibroblast formation in CFs isolated from the human failing heart.
    CONCLUSIONS: These results define glutaminolysis as necessary for myofibroblast formation and persistence, providing substantial rationale to evaluate several new therapeutic targets to treat cardiac fibrosis.
    Keywords:  Epigenetics; Fibrosis; Glutamine; Heart failure; Metabolism; Myofibroblast
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.08.002
  7. Cell Death Dis. 2022 Aug 24. 13(8): 730
    Glycosylation defects, offset by PEPCK-M, drive entosis in breast carcinoma cells.
    Petra Hyroššová, Marc Aragó, Cristina Muñoz-Pinedo, Francesc Viñals, Pablo M García-Rovés, Carmen Escolano, Andrés Méndez-Lucas, Jose C Perales.
      On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we presumed that PEPCK-M could play a role in this process by offsetting key metabolites into glycosyl moieties using alternative substrates. PEPCK-M inhibition using iPEPCK-2 promoted entosis in the absence of glucose, whereas its overexpression inhibited entosis. PEPCK-M inhibition had a direct role on total protein glycosylation as determined by Concanavalin A binding, and the specific ratio of fully glycosylated LAMP1 or E-cadherin. The content of metabolites, and the fluxes from 13C-glutamine label into glycolytic intermediates up to glucose-6-phosphate, and ribose- and ribulose-5-phosphate, was dependent on PEPCK-M content as measured by GC/MS. All in all, we demonstrate for the first time that protein glycosylation defects precede and initiate the entosis process and implicates PEPCK-M in this survival program to dampen the consequences of glucose deprivation. These results have broad implications to our understanding of tumor metabolism and treatment strategies.
    DOI:  https://doi.org/10.1038/s41419-022-05177-x
  8. J Pers Med. 2022 Aug 18. pii: 1329. [Epub ahead of print]12(8):
    MicroRNAs as Regulators of Cancer Cell Energy Metabolism.
    Natarajaseenivasan Suriya Muthukumaran, Prema Velusamy, Charles Solomon Akino Mercy, Dianne Langford, Kalimuthusamy Natarajaseenivasan, Santhanam Shanmughapriya.
      To adapt to the tumor environment or to escape chemotherapy, cancer cells rapidly reprogram their metabolism. The hallmark biochemical phenotype of cancer cells is the shift in metabolic reprogramming towards aerobic glycolysis. It was thought that this metabolic shift to glycolysis alone was sufficient for cancer cells to meet their heightened energy and metabolic demands for proliferation and survival. Recent studies, however, show that cancer cells rely on glutamine, lipid, and mitochondrial metabolism for energy. Oncogenes and scavenging pathways control many of these metabolic changes, and several metabolic and tumorigenic pathways are post-transcriptionally regulated by microRNA (miRNAs). Genes that are directly or indirectly responsible for energy production in cells are either negatively or positively regulated by miRNAs. Therefore, some miRNAs play an oncogenic role by regulating the metabolic shift that occurs in cancer cells. Additionally, miRNAs can regulate mitochondrial calcium stores and energy metabolism, thus promoting cancer cell survival, cell growth, and metastasis. In the electron transport chain (ETC), miRNAs enhance the activity of apoptosis-inducing factor (AIF) and cytochrome c, and these apoptosome proteins are directed towards the ETC rather than to the apoptotic pathway. This review will highlight how miRNAs regulate the enzymes, signaling pathways, and transcription factors of cancer cell metabolism and mitochondrial calcium import/export pathways. The review will also focus on the metabolic reprogramming of cancer cells to promote survival, proliferation, growth, and metastasis with an emphasis on the therapeutic potential of miRNAs for cancer treatment.
    Keywords:  TCA; cancer metabolism; fatty acid oxidation; glucose oxidation; miRNA; pentose-phosphate pathway
    DOI:  https://doi.org/10.3390/jpm12081329
  9. Front Bioeng Biotechnol. 2022 ;10 943906
    Nanomedicines Targeting Metabolism in the Tumor Microenvironment.
    Mengdi Ren, Xiaoqiang Zheng, Huan Gao, Aimin Jiang, Yu Yao, Wangxiao He.
      Cancer cells reprogram their metabolism to meet their growing demand for bioenergy and biosynthesis. The metabolic profile of cancer cells usually includes dysregulation of main nutritional metabolic pathways and the production of metabolites, which leads to a tumor microenvironment (TME) having the characteristics of acidity, hypoxic, and/or nutrient depletion. Therapies targeting metabolism have become an active and revolutionary research topic for anti-cancer drug development. The differential metabolic vulnerabilities between tumor cells and other cells within TME provide nanotechnology a therapeutic window of anti-cancer. In this review, we present the metabolic characteristics of intrinsic cancer cells and TME and summarize representative strategies of nanoparticles in metabolism-regulating anti-cancer therapy. Then, we put forward the challenges and opportunities of using nanoparticles in this emerging field.
    Keywords:  cancer treatment; metabolic reprograming; metabolism; nanomedicine; tumor microenvironment
    DOI:  https://doi.org/10.3389/fbioe.2022.943906
  10. Genes (Basel). 2022 Aug 01. pii: 1375. [Epub ahead of print]13(8):
    miR-23b-3p Modulating Cytoprotective Autophagy and Glutamine Addiction in Sorafenib Resistant HepG2, a Hepatocellular Carcinoma Cell Line.
    Ramanpreet Kaur, Shruthi Kanthaje, Sunil Taneja, Radha K Dhiman, Anuradha Chakraborti.
      BACKGROUND: Hepatocellular carcinoma (HCC) is the second most common malignancy with increasing cancer deaths worldwide. HCC is mainly diagnosed at its advanced stage, and treatment with FDA-approved sorafenib, the multikinase inhibitor drug, is advised. Acquired resistance against sorafenib develops through several pathways involving hypoxia, autophagy, high glycolysis, or glutaminolysis. Small non-coding RNAs, similar to microRNAs (miRNAs), are also known to affect sorafenib resistance in HCC. However, there is a lack of information regarding the significance of differentially expressed miRNA (if any) on autophagy and glutamine regulation in sorafenib-resistant HCC.METHODS: The expression of autophagy and glutaminolysis genes was checked in both parental and sorafenib resistant HepG2 cell lines by real-time PCR. MTT and Annexin/PI assays were also performed in the presence of inhibitors such as chloroquine (autophagy inhibitor) and BPTES (glutaminolysis inhibitor). Next generation sequencing and in silico analysis were performed to select autophagy and glutamine addiction-specific microRNA. Selected miRNA were transfected into both HepG2 cells to examine its effect on autophagy and glutamine addiction in regulating sorafenib-resistant HCC.
    RESULTS: Our in vitro study depicted a higher expression of genes encoding autophagy and glutaminolysis in sorafenib-resistant HepG2 cells. Moreover, inhibitors for autophagy (chloroquine) and glutaminolysis (BPTES) showed a diminished level of cell viability and augmentation in cell apoptosis of sorafenib-resistant HepG2 cells. NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results.
    CONCLUSION: Our study highlights the cytoprotective role of autophagy and glutamine addiction modulated by miR-23b-3p (tumor suppressor), suggesting new approaches to curb sorafenib resistance in HCC.
    Keywords:  autophagy; glutamine addiction; hepatocellular carcinoma; miR-23b-3p; sorafenib resistance
    DOI:  https://doi.org/10.3390/genes13081375
  11. Int J Environ Res Public Health. 2022 Aug 18. pii: 10261. [Epub ahead of print]19(16):
    Commonalities in Metabolic Reprogramming between Tobacco Use and Oral Cancer.
    Blake R Rushing, Spencer Tilley, Sabrina Molina, Madison Schroder, Susan Sumner.
      Tobacco use is a major public health concern and is linked to myriad diseases, including cancer. The link between tobacco use and oral cancer, specifically, is very strong, making tobacco use one of the primary risk factors for oral cancer. While this association is well known, the underlying biochemical changes that result from tobacco use, and how this links to metabolic phenotypes of oral cancer, is not well understood. To address this knowledge gap, a combination of literature reviews and metabolomics studies were performed to identify commonalities in metabolic perturbations between tobacco use and oral cancers. Metabolomics analysis was performed on pooled reference urine from smokers and non-smokers, healthy and malignant oral tissues, and cultured oral cells with or without treatment of the well-known tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Alterations in amino acid metabolism, carbohydrates/oxidative phosphorylation, fatty acid oxidation, nucleotide metabolism, steroid metabolism, and vitamin metabolism were found to be shared between tobacco use and oral cancer. These results support the conclusion that tobacco use metabolically reprograms oral cells to support malignant transformation through these pathways. These metabolic reprogramming events may be potential targets to prevent or treat oral cancers that arise from tobacco use.
    Keywords:  cancer; carcinogen; metabolic reprogramming; metabolism; metabolomics; oral cancer; smoking; tobacco use
    DOI:  https://doi.org/10.3390/ijerph191610261
  12. Front Immunol. 2022 ;13 909580
    Metabolic rewiring directs melanoma immunology.
    Ningyue Sun, Yangzi Tian, Yuhan Chen, Weinan Guo, Chunying Li.
      Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.
    Keywords:  glycolysis; immunology; immunotherapy; melanoma; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.909580
  13. Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2205456119
    Metastatic triple negative breast cancer adapts its metabolism to destination tissues while retaining key metabolic signatures.
    Fariba Roshanzamir, Jonathan L Robinson, Daniel Cook, Mohammad Hossein Karimi-Jafari, Jens Nielsen.
      Triple negative breast cancer (TNBC) metastases are assumed to exhibit similar functions in different organs as in the original primary tumor. However, studies of metastasis are often limited to a comparison of metastatic tumors with primary tumors of their origin, and little is known about the adaptation to the local environment of the metastatic sites. We therefore used transcriptomic data and metabolic network analyses to investigate whether metastatic tumors adapt their metabolism to the metastatic site and found that metastatic tumors adopt a metabolic signature with some similarity to primary tumors of their destinations. The extent of adaptation, however, varies across different organs, and metastatic tumors retain metabolic signatures associated with TNBC. Our findings suggest that a combination of anti-metastatic approaches and metabolic inhibitors selected specifically for different metastatic sites, rather than solely targeting TNBC primary tumors, may constitute a more effective treatment approach.
    Keywords:  gene expression; genome-scale metabolic models; metastasis; systems biology; triple negative breast cancer
    DOI:  https://doi.org/10.1073/pnas.2205456119
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