bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–09–22
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
  2. Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective.
  3. Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
  4. Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
  5. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
  6. Advancements in Targeted Therapeutics: Integrating Metabolic Modulation, Immune Engineering, and Biologic Formulation Technologies.
  7. Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell.
  8. Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus.
  9. From Inception to Malignancy: the Co-evolution of Pancreatic Cancer and Its Immunosuppressive Microenvironment.
  10. Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing anti-tumor immunity.
  11. Technologies for Decoding Cancer Metabolism with Spatial Resolution.
  12. Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.
  13. Lipid-laden macrophages recycle myelin to feed glioblastoma.
  1. Dis Model Mech. 2024 Sep 01. pii: dmm050814. [Epub ahead of print]17(9):
    Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.
    Patrick B Jonker, Alexander Muir.
      Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.
    Keywords:  Acidosis; Diet; Hypoxia; Lipid metabolism; Nutrient deprivation; Tumor microenvironment
    DOI:  https://doi.org/10.1242/dmm.050814
  2. Mol Cancer. 2024 Sep 18. 23(1): 202
    Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective.
    Yang Xiao, Yongsheng Li, Huakan Zhao.
      Metabolic reprogramming drives the development of an immunosuppressive tumor microenvironment (TME) through various pathways, contributing to cancer progression and reducing the effectiveness of anticancer immunotherapy. However, our understanding of the metabolic landscape within the tumor-immune context has been limited by conventional metabolic measurements, which have not provided comprehensive insights into the spatiotemporal heterogeneity of metabolism within TME. The emergence of single-cell, spatial, and in vivo metabolomic technologies has now enabled detailed and unbiased analysis, revealing unprecedented spatiotemporal heterogeneity that is particularly valuable in the field of cancer immunology. This review summarizes the methodologies of metabolomics and metabolic regulomics that can be applied to the study of cancer-immunity across single-cell, spatial, and in vivo dimensions, and systematically assesses their benefits and limitations.
    Keywords:  Cancer-immunity; Immunometabolism; Metabolic regulomics; Metabolomics; Single cell; Spatiotemporal omics
    DOI:  https://doi.org/10.1186/s12943-024-02113-9
  3. Cell Biol Int. 2024 Sep 16.
    Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
    Abhishek Choudhury, Soumya Chatterjee, Shauryabrota Dalui, Pronabesh Ghosh, Altamas Hossain Daptary, Golam Kibria Mollah, Arindam Bhattacharyya.
      Cytotoxic CD8+ T cells plays a pivotal role in the adaptive immune system to protect the organism against infections and cancer. During activation and response, T cells undergo a metabolic reprogramming that involves various metabolic pathways, with a predominant reliance on glycolysis to meet their increased energy demands and enhanced effector response. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Recent reports indicates that exosomes may transfer biologically functional molecules to the recipient cells, thereby facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells. This study sought to enlighten possible involvement of cancer-derived exosomes in CD8 + T cell glucose metabolism and discover a regulated signalome as a mechanism of action. We observed reduction in glucose metabolism due to downregulation of AKT/mTOR signalome in activated CD8 + T cells after cancer derived exosome exposure. In-vivo murine breast tumor studies showed better tumor control and antitumor CD8 + T cell glycolysis and effector response after abrogation of exosome release from breast cancer cells. Summarizing, the present study establishes an immune evasion mechanism of breast cancer cell secreted exosomes that will act as a foundation for future precision cancer therapeutics.
    Keywords:  CD8 + T cells; breast cancer; effector response; exhaustion; exosomes; glycolysis
    DOI:  https://doi.org/10.1002/cbin.12241
  4. Cancer Res. 2024 Sep 16. 84(18): 2947-2949
    Nutrient Levels and Nutrient Sources in Pancreatic Tumors.
    Sven Groessl, Wilhelm Palm.
      It has been known that poor tumor perfusion and dysregulated cancer cell metabolism give rise to tumor microenvironments with unphysiologic nutrient levels, but the precise alterations in metabolite abundance are not well defined. In a 2015 study in Cancer Research, Kamphorst and colleagues published a detailed comparison of the metabolome from human pancreatic tumors and benign tissues. Tumors were depleted in glucose and various nonessential amino acids but, surprisingly, enriched in essential amino acids. The authors attributed these nutrient imbalances to macropinocytosis of extracellular proteins, a RAS-driven amino acid acquisition pathway that was found to be increased in human tumors and supports pancreatic cancer cell growth during amino acid starvation. These findings substantially contributed to the understanding of altered nutrient levels in tumors and extracellular proteins as noncanonical nutrients. Intratumoral nutrient levels in different cancer contexts and signaling pathways that regulate nutrient acquisition by cancer cells remain a focus of current research. See related article by Kamphorst and colleagues, Cancer Res 2015;75:544-53.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2447
  5. Cell. 2024 Sep 12. pii: S0092-8674(24)00956-5. [Epub ahead of print]
    Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.
    Jeremy G Baldwin, Christoph Heuser-Loy, Tanmoy Saha, Roland C Schelker, Dragana Slavkovic-Lukic, Nicholas Strieder, Inmaculada Hernandez-Lopez, Nisha Rana, Markus Barden, Fabio Mastrogiovanni, Azucena Martín-Santos, Andrea Raimondi, Philip Brohawn, Brandon W Higgs, Claudia Gebhard, Veena Kapoor, William G Telford, Sanjivan Gautam, Maria Xydia, Philipp Beckhove, Sina Frischholz, Kilian Schober, Zacharias Kontarakis, Jacob E Corn, Matteo Iannacone, Donato Inverso, Michael Rehli, Jessica Fioravanti, Shiladitya Sengupta, Luca Gattinoni.
      Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
    Keywords:  CAR T therapy; CD8(+) T cells; TCR-T therapy; TIL therapy; Talin 2; bone marrow stromal cells; cancer immunotherapy; immune metabolism; mitochondrial transfer; nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2024.08.029
  6. ACS Med Chem Lett. 2024 Sep 12. 15(9): 1430-1432
    Advancements in Targeted Therapeutics: Integrating Metabolic Modulation, Immune Engineering, and Biologic Formulation Technologies.
    Robert B Kargbo.
      The rapid advancement of targeted therapeutics has significantly improved treatment precision and efficacy in oncology and metabolic disorders. This article integrates key developments in four areas: highly selective PPAR modulators for metabolic and inflammatory diseases; CRISPR-engineered T-cell receptor therapies targeting the KRAS G12D mutation in cancer; strategies to enhance antitumor immunity through glutamine metabolism modulation in the tumor microenvironment; and a novel system for analyzing coformulated biologics. These innovations highlight the integration of metabolic modulation, immune system engineering, and advanced biologic formulation, paving the way for more effective and personalized therapeutic approaches.
    DOI:  https://doi.org/10.1021/acsmedchemlett.4c00404
  7. Cell Rep Med. 2024 Sep 17. pii: S2666-3791(24)00439-7. [Epub ahead of print]5(9): 101718
    Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell.
    Yang Yang, Tianduo Pei, Xiaolin Hu, Yu Lu, Yanqiu Huang, Tingya Wan, Chaobao Liu, Fengqian Chen, Bao Guo, Yuemei Hong, Qian Ba, Xiaoguang Li, Hui Wang.
      The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8+ T cell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ T cell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101718
  8. Int J Cancer. 2024 Sep 18.
    Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus.
    Shen-Han Lee, Alan Soo-Beng Khoo, John R Griffiths, Norhafiza Mat Lazim.
      The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.
    Keywords:  EBV‐associated malignancies; Epstein–Barr virus; nasopharyngeal cancer; tumour metabolism; tumour microenvironment
    DOI:  https://doi.org/10.1002/ijc.35192
  9. Cancer Res. 2024 Sep 16. 84(18): 2944-2946
    From Inception to Malignancy: the Co-evolution of Pancreatic Cancer and Its Immunosuppressive Microenvironment.
    Filip Bednar, Lee Y Olsen, Marina Pasca di Magliano.
      Published in Cancer Research in 2007, Clark and colleagues first introduced the concept that the immune microenvironment evolves in lockstep with the progression of pancreatic cancer. Leveraging genetically engineered mouse models of the disease that were described a few years earlier, Clark and colleagues used a combination of approaches to describe the dynamics of immune evolution in precursor lesions all the way to overt malignancy. They discovered that immunosuppression is established at the earliest stages of carcinogenesis. Here, we discuss their findings, how they led to a wealth of functional work, and how they have been expanded upon since the advent of -omics technologies. See related article by Clark and colleagues, Cancer Res 2007;67:9518-27.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2732
  10. JCI Insight. 2024 Sep 19. pii: e178644. [Epub ahead of print]
    Pivotal roles for cancer cell-intrinsic mPGES-1 and autocrine EP4 signaling in suppressing anti-tumor immunity.
    Nune Markosyan, Il-Kyu Kim, Charu Arora, Liz Quinones-Ware, Nikhil Joshi, Noah C Cheng, Emma Y Schechter, John W Tobias, Joseph E Hochberg, Emily Corse, Kang Liu, Varenka Rodriguez DiBlasi, Li-Chuan Chan, Emer M Smyth, Garret A Fitzgerald, Ben Z Stanger, Robert H Vonderheide.
      Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME) by acting on the immune cells, but the impact of PGE2 signaling in tumor cells on immunosuppressive TME is unclear. We demonstrate that deleting the PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME, activates T cells, and suppresses tumor growth. Knockout (KO) of Ptges (the gene encoding PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D/P53R172H/Yfp/CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges and Ptger4 KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4 KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a non-redundant role for the autocrine mPGES1-PGE2-EP4 signaling axis in pancreatic cancer cells - further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.
    Keywords:  Cancer immunotherapy; Eicosanoids; Immunology; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.178644
  11. Cold Spring Harb Perspect Med. 2024 Sep 16. pii: a041553. [Epub ahead of print]
    Technologies for Decoding Cancer Metabolism with Spatial Resolution.
    Walter W Chen, Michael E Pacold, David M Sabatini, Naama Kanarek.
      It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.
    DOI:  https://doi.org/10.1101/cshperspect.a041553
  12. Trends Cancer. 2024 Sep 13. pii: S2405-8033(24)00172-9. [Epub ahead of print]
    Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes.
    Benjamin N Gantner, Flavio R Palma, Madhura R Pandkar, Marcelo J Sakiyama, Daniel Arango, Gina M DeNicola, Ana P Gomes, Marcelo G Bonini.
      Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes.
    Keywords:  cancer metabolism; epigenetics; histones; metabolites; novel therapeutics; post-translational modifications
    DOI:  https://doi.org/10.1016/j.trecan.2024.08.005
  13. Cancer Res. 2024 Sep 18.
    Lipid-laden macrophages recycle myelin to feed glioblastoma.
    Lizhi Pang, Fei Zhou, Peiwen Chen.
      Tumor-associated microglia and macrophages (TAMs) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment (TME). Given the heterogeneity and plasticity of TAMs in the GBM TME, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman and colleagues identified a subpopulation of GPNMBhigh lipid-laden microglia and macrophages (LLMs) in GBM. Mesenchymal-like (MES-like) GBM cells help to generate the LLM phenotype. Reciprocally, LLMs are epigenetically rewired to recycle myelin and transfer the lipid from myelin to cancer cells, fueling MES-like GBM progression in an LXR/ABCA1-dependent manner. Together, leveraging LLMs opens new therapeutic possibilities for rewiring the metabolism-mediated tumor-TAM interaction during GBM progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3362
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