bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023‒03‒05
fourteen papers selected by
Linda Chan
Cleveland Clinic
  1. What is cancer metabolism?
  2. Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions.
  3. Systematic diet composition swap in a mouse genome-scale metabolic model reveals determinants of obesogenic diet metabolism in liver cancer.
  4. A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
  5. Metabolic Rewiring and Stemness: A Critical attribute of Pancreatic Cancer Progression.
  6. Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma.
  7. MAEL facilitates metabolic reprogramming and breast cancer progression by promoting the degradation of citrate synthase and fumarate hydratase via chaperone-mediated autophagy.
  8. Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
  9. Ras protein abundance correlates with Ras isoform mutation patterns in cancer.
  10. Metabolic activity grows in human cancers pushed by phenotypic variability.
  11. Bleb protrusions help cancer cells to cheat death.
  12. NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
  13. Polyunsaturated fatty acid-bound alpha-fetoprotein promotes immune suppression by altering human dendritic cell metabolism.
  14. Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response.
  1. Cell. 2023 Feb 22. pii: S0092-8674(23)00097-1. [Epub ahead of print]
    What is cancer metabolism?
    Lydia W S Finley.
      The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While many studies of cell metabolism focus on cancer cells, the principles of metabolism elucidated in cancer cells apply to a wide range of mammalian cells. The goal of this review is to discuss how the field of cancer metabolism provides a framework for revealing principles of cell metabolism and for dissecting the metabolic networks that allow cells to meet their specific demands. Understanding context-specific metabolic preferences and liabilities will unlock new approaches to target cancer cells to improve patient care.
    DOI:  https://doi.org/10.1016/j.cell.2023.01.038
  2. Cell Rep. 2023 Feb 26. pii: S2211-1247(23)00164-X. [Epub ahead of print]42(3): 112153
    Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions.
    Leticia Soriano-Baguet, Melanie Grusdat, Henry Kurniawan, Mohaned Benzarti, Carole Binsfeld, Anouk Ewen, Joseph Longworth, Lynn Bonetti, Luana Guerra, Davide G Franchina, Takumi Kobayashi, Veronika Horkova, Charlène Verschueren, Sergio Helgueta, Deborah Gérard, Tushar H More, Antonia Henne, Catherine Dostert, Sophie Farinelle, Antoine Lesur, Jean-Jacques Gérardy, Christian Jäger, Michel Mittelbronn, Lasse Sinkkonen, Karsten Hiller, Johannes Meiser, Dirk Brenner.
      Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.
    Keywords:  CP: Immunology; CP: Metabolism; IL-17; T cells; Th17 cells; acetyl-CoA; citrate; epigenetics; experimental autoimmune encephalomyelitis; glucose metabolism; histone acetylation; pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112153
  3. iScience. 2023 Feb 17. 26(2): 106040
    Systematic diet composition swap in a mouse genome-scale metabolic model reveals determinants of obesogenic diet metabolism in liver cancer.
    Frederick Clasen, Patrícia M Nunes, Gholamreza Bidkhori, Nourdine Bah, Stefan Boeing, Saeed Shoaie, Dimitrios Anastasiou.
      Dietary nutrient availability and gene expression, together, influence tissue metabolic activity. Here, we explore whether altering dietary nutrient composition in the context of mouse liver cancer suffices to overcome chronic gene expression changes that arise from tumorigenesis and western-style diet (WD). We construct a mouse genome-scale metabolic model and estimate metabolic fluxes in liver tumors and non-tumoral tissue after computationally varying the composition of input diet. This approach, called Systematic Diet Composition Swap (SyDiCoS), revealed that, compared to a control diet, WD increases production of glycerol and succinate irrespective of specific tissue gene expression patterns. Conversely, differences in fatty acid utilization pathways between tumor and non-tumor liver are amplified with WD by both dietary carbohydrates and lipids together. Our data suggest that combined dietary component modifications may be required to normalize the distinctive metabolic patterns that underlie selective targeting of tumor metabolism.
    Keywords:  Biological sciences; Cancer; Cellular physiology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.106040
  4. bioRxiv. 2023 Feb 23. pii: 2023.02.22.529581. [Epub ahead of print]
    A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
    Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Henar Cuervo Grajal, Dominique M O Higgins, Colin P Sperring, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang T T Nguyen, Peter B Wu, Li Hai, Charles Karan, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter D Canoll.
      Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.
    DOI:  https://doi.org/10.1101/2023.02.22.529581
  5. Stem Cells. 2023 Mar 04. pii: sxad017. [Epub ahead of print]
    Metabolic Rewiring and Stemness: A Critical attribute of Pancreatic Cancer Progression.
    Ayoola O Ogunleye, Rama Krishna Nimmakayala, Surinder K Batra, Moorthy P Ponnusamy.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases with a poor 5-year survival rate. PDAC cells rely on various metabolic pathways to fuel their unlimited proliferation and metastasis. Reprogramming glucose, fatty acid, amino acid, and nucleic acid metabolisms contributes to PDAC cell growth. Cancer stem cells are the primary cell types that play a critical role in the progression and aggressiveness of PDAC. Emerging studies indicate that the cancer stem cells in PDAC tumors are heterogeneous and show specific metabolic dependencies. In addition, understanding specific metabolic signatures and factors that regulate these metabolic alterations in the cancer stem cells of PDAC paves the way for developing novel therapeutic strategies targeting CSCs. In this review, we discuss the current understanding of PDAC metabolism by specifically exploring the metabolic dependencies of cancer stem cells. We also review the current knowledge of targeting these metabolic factors that regulate CSC maintenance and PDAC progression.
    Keywords:  Pancreatic cancer; cancer stem cells; metabolism; targeting metabolic pathways
    DOI:  https://doi.org/10.1093/stmcls/sxad017
  6. bioRxiv. 2023 Feb 22. pii: 2023.02.22.529457. [Epub ahead of print]
    Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma.
    Natthakan Thongon, Feiyang Ma, Pamela Lockyer, Natalia Baran, Jintan Liu, Christopher Jackson, Ashley Rose, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Nicola Giuliani, Irene Ganan-Gomez, Vera Adema, Yun Qing, Min Ha, Rodrigo Fonseca, Caleb Class, Lin Tan, Rashmi Kanagal-Shamanna, David Berrios Nolasco, Claudio Cerchione, Guillermo Montalban-Bravo, Andrea Santoni, Carlos Bueso-Ramos, Marina Konopleva, Philip Lorenzi, Guillermo Garcia-Manero, Elisabeth Manasanch, Andrea Viale, Marta Chesi, Simona Colla.
      DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.STATEMENT OF SIGNIFICANCE: Metabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.
    DOI:  https://doi.org/10.1101/2023.02.22.529457
  7. FEBS J. 2023 Mar 03.
    MAEL facilitates metabolic reprogramming and breast cancer progression by promoting the degradation of citrate synthase and fumarate hydratase via chaperone-mediated autophagy.
    Lin Zhou, Shuobo Ou, Ting Liang, Meiling Li, Pei Xiao, Jiaxin Cheng, Jianlin Zhou, Liqin Yuan.
      Metabolic reprogramming is a hallmark of cancer. Several studies have shown that inactivation of Krebs cycle enzymes, such as citrate synthase (CS) and fumarate hydratase (FH), facilitates aerobic glycolysis and cancer progression. MAEL has been shown to play an oncogenic role in bladder, liver, colon and gastric cancers, but its role in breast cancer and metabolism is still unknown. Here, we demonstrated that MAEL promoted malignant behaviors and aerobic glycolysis in breast cancer cells. Mechanistically, MAEL interacted with CS/FH and HSAP8 via its MAEL domain and HMG domain, respectively, and then enhanced the binding affinity of CS/FH with HSPA8, facilitating the transport of CS/FH to the lysosome for degradation. MAEL-induced degradation of CS and FH could be suppressed by the lysosome inhibitors leupeptin and NH4 Cl, but not by the macroautophagy inhibitor 3-MA or the proteasome inhibitor MG132. These results suggested that MAEL promoted the degradation of CS and FH via chaperone-mediated autophagy (CMA). Further studies showed that the expression of MAEL was significantly and negatively correlated with CS and FH in breast cancer. Moreover, overexpression of CS or/and FH could reverse the oncogenic effects of MAEL. Taken together, MAEL promotes a metabolic shift from oxidative phosphorylation to glycolysis by inducing CMA-dependent degradation of CS and FH, thereby promoting breast cancer progression. These findings have elucidated a novel molecular mechanism of MAEL in cancer.
    Keywords:  MAEL; breast cancer; chaperone-mediated autophagy; citrate synthase; fumarate hydratase; metabolic reprogramming
    DOI:  https://doi.org/10.1111/febs.16768
  8. Cancer Res. 2023 Mar 02. pii: CAN-22-3000. [Epub ahead of print]
    Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
    Sang Jun Yoon, Joseph A Combs, Aimee Falzone, Nicolas Prieto-Farigua, Samantha Caldwell, Hayley D Ackerman, Elsa R Flores, Gina M DeNicola.
      Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and cancers that arise from them using stable isotope 13C1-serine and 13C6-cystine tracing. De novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. However, differences in glutathione labeling from cysteine were evident across tumor types. Thus, cystine is a major contributor to the cysteine pool in tumors, and glutathione metabolism is differentially active across tumor types.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3000
  9. Oncogene. 2023 Mar 02.
    Ras protein abundance correlates with Ras isoform mutation patterns in cancer.
    Fiona E Hood, Yasmina M Sahraoui, Rosalind E Jenkins, Ian A Prior.
      Activating mutations of Ras genes are often observed in cancer. The protein products of the three Ras genes are almost identical. However, for reasons that remain unclear, KRAS is far more frequently mutated than the other Ras isoforms in cancer and RASopathies. We have quantified HRAS, NRAS, KRAS4A and KRAS4B protein abundance across a large panel of cell lines and healthy tissues. We observe consistent patterns of KRAS > NRAS»HRAS protein expression in cells that correlate with the rank order of Ras mutation frequencies in cancer. Our data provide support for the model of a sweet-spot of Ras dosage mediating isoform-specific contributions to cancer and development. We suggest that in most cases, being the most abundant Ras isoform correlates with occupying the sweet-spot and that HRAS and NRAS expression is usually insufficient to promote oncogenesis when mutated. However, our results challenge the notion that rare codons mechanistically underpin the predominance of KRAS mutant cancers. Finally, direct measurement of mutant versus wildtype KRAS protein abundance revealed a frequent imbalance that may suggest additional non-gene duplication mechanisms for optimizing oncogenic Ras dosage.
    DOI:  https://doi.org/10.1038/s41388-023-02638-1
  10. iScience. 2023 Mar 17. 26(3): 106118
    Metabolic activity grows in human cancers pushed by phenotypic variability.
    Jesús J Bosque, Gabriel F Calvo, David Molina-García, Julián Pérez-Beteta, Ana M García Vicente, Víctor M Pérez-García.
      Different evolutionary processes push cancers to increasingly aggressive behaviors, energetically sustained by metabolic reprogramming. The collective signature emerging from this transition is macroscopically displayed by positron emission tomography (PET). In fact, the most readily PET measure, the maximum standardized uptake value (SUVmax), has been found to have prognostic value in different cancers. However, few works have linked the properties of this metabolic hotspot to cancer evolutionary dynamics. Here, by analyzing diagnostic PET images from 512 patients with cancer, we found that SUVmax scales superlinearly with the mean metabolic activity (SUVmean), reflecting a dynamic preferential accumulation of activity on the hotspot. Additionally, SUVmax increased with metabolic tumor volume (MTV) following a power law. The behavior from the patients data was accurately captured by a mechanistic evolutionary dynamics model of tumor growth accounting for phenotypic transitions. This suggests that non-genetic changes may suffice to fuel the observed sustained increases in tumor metabolic activity.
    Keywords:  Cancer; Cancer systems biology; Human metabolism; Mathematical biosciences
    DOI:  https://doi.org/10.1016/j.isci.2023.106118
  11. Nature. 2023 Mar 01.
    Bleb protrusions help cancer cells to cheat death.
    Michal Reichman-Fried, Erez Raz.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-023-00477-4
  12. Cell Metab. 2023 Feb 22. pii: S1550-4131(23)00012-8. [Epub ahead of print]
    NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
    Tommy Weiss-Sadan, Maolin Ge, Makiko Hayashi, Magdy Gohar, Cong-Hui Yao, Adriaan de Groot, Stefan Harry, Alexander Carlin, Hannah Fischer, Lei Shi, Ting-Yu Wei, Charles H Adelmann, Konstantin Wolf, Tristan Vornbäumen, Benedikt R Dürr, Mariko Takahashi, Marianne Richter, Junbing Zhang, Tzu-Yi Yang, Vindhya Vijay, David E Fisher, Aaron N Hata, Marcia C Haigis, Raul Mostoslavsky, Nabeel Bardeesy, Thales Papagiannakopoulos, Liron Bar-Peled.
      Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.
    Keywords:  NADH/NAD(+); NRF2-KEAP1 pathway; functional genomic; non-small cell lung cancer; oxidative phosphorylation; reductive stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.012
  13. Cancer Res. 2023 Feb 27. pii: CAN-22-3551. [Epub ahead of print]
    Polyunsaturated fatty acid-bound alpha-fetoprotein promotes immune suppression by altering human dendritic cell metabolism.
    Paul V Munson, Juraj Adamik, Felix J Hartmann, Patricia M B Favaro, Daniel Ho, Sean C Bendall, Alexis J Combes, Matthew F Krummel, Karen Zhang, Robin K Kelley, Lisa H Butterfield.
      Alpha-fetoprotein (AFP) is expressed by stem-like and poor outcome hepatocellular cancer tumors and is a clinical tumor biomarker. AFP has been demonstrated to inhibit dendritic cell differentiation and maturation and to block oxidative phosphorylation. To identify the critical metabolic pathways leading to human dendritic cell functional suppression, here we utilized two recently described single cell profiling methods, scMEP (single-cell metabolic profiling) and SCENITH (single-cell energetic metabolism by profiling translation inhibition). Glycolytic capacity and glucose dependence of dendritic cells was significantly increased by tumor-derived, but not normal cord blood-derived, AFP, leading to increased glucose uptake and lactate secretion. Key molecules in the electron transport chain in particular were regulated by tumor-derived AFP. These metabolic changes occurred at mRNA and protein levels, with negative impact on dendritic cell stimulatory capacity. Tumor-derived AFP bound significantly more polyunsaturated fatty acids than cord blood-derived AFP. Polyunsaturated fatty acids bound to AFP increased metabolic skewing and promoted dendritic cell functional suppression. Polyunsaturated fatty acids inhibited dendritic cell differentiation in vitro, and ω-6 polyunsaturated fatty acids conferred potent immunoregulation when bound to tumor-derived AFP. Together, these findings provide mechanistic insights into how AFP antagonizes the innate immune response to limit anti-tumor immunity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3551
  14. Cell Rep. 2023 Mar 03. pii: S2211-1247(23)00197-3. [Epub ahead of print]42(3): 112186
    Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8+ T cells with enhanced effector function and anti-tumor response.
    Cheng-Cheng Yao, Rui-Ming Sun, Yi Yang, Hai-Yan Zhou, Zhou-Wenli Meng, Rui Chi, Li-Liang Xia, Ping Ji, Ying-Ying Chen, Guo-Qing Zhang, Hai-Peng Sun, Shun Lu, Chen Yang, Ying Wang.
      Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8+ T cell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8+ T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8+ T cells and enhanced anti-tumor immunity. CD8+ T cells from PP2Cm-/- mice upregulate glucose transporter Glut1 expression in a FoxO1-dependent manner with more glucose uptake, as well as increased glycolysis and oxidative phosphorylation. Moreover, BCAA supplementation recapitulates CD8+ T cell hyper-functions and synergizes with anti-PD-1, in line with a better prognosis in NSCLC patients containing high BCAAs when receiving anti-PD-1 therapy. Our finding thus reveals that accumulation of BCAAs promotes effector function and anti-tumor immunity of CD8+ T cells through reprogramming glucose metabolism, making BCAAs alternative supplementary components to increase the clinical efficacy of anti-PD-1 immunotherapy against tumors.
    Keywords:  CD8(+) T cells; CP: Immunology; anti-tumor immunity; branched-chain amino acid accumulation; effector function; glucose metabolism; synergy with anti-PD-1 treatment
    DOI:  https://doi.org/10.1016/j.celrep.2023.112186
This page is being maintained by Thomas Krichel. It was last updated on 2023‒03‒06 at 02:12:09.