bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023‒05‒14
eight papers selected by
Oltea Sampetrean, Keio University
  1. Inosine Induces Stemness Features in CAR T cells and Enhances Potency.
  2. The role and metabolic adaptations of neutrophils in premetastatic niches.
  3. T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade.
  4. Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.
  5. GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.
  6. NAD + Metabolism Generates a Metabolic Vulnerability in Endocrine-Resistant Metastatic Breast Tumors in Females.
  7. MetaTiME integrates single-cell gene expression to characterize the meta-components of the tumor immune microenvironment.
  8. Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion.
  1. bioRxiv. 2023 Apr 25. pii: 2023.04.21.537859. [Epub ahead of print]
    Inosine Induces Stemness Features in CAR T cells and Enhances Potency.
    Dorota D Klysz, Carley Fowler, Meena Malipatlolla, Lucille Stuani, Katherine A Freitas, Stefanie Meier, Bence Daniel, Katalin Sandor, Peng Xu, Jing Huang, Louai Labanieh, Amaury Leruste, Malek Bashti, Vimal Keerthi, Janette Mata-Alcazar, Nikolaos Gkitsas, Justin A Guerrero, Chris Fisher, Sunny Patel, Kyle Asano, Shabnum Patel, Kara L Davis, Ansuman T Satpathy, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 + CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.Statement of Significance: Adenosine is well known to inhibit T cell function and substantial effort has focused on inhibiting adenosine generation and signaling. Here, we show that exhausted T cells are suppressed by adenosine, which is only modestly impacted by inhibiting adenosine generation or signaling. In contrast, metabolism of adenosine to inosine augmented T cell function and culture of T cells with inosine induced multi-level reprogramming leading to stemness and improved anti-tumor potency. We demonstrate the feasibility of introducing inosine during GMP cell manufacturing as a novel strategy to generate enhanced CAR-T cells.
    DOI:  https://doi.org/10.1101/2023.04.21.537859
  2. Biomark Res. 2023 May 09. 11(1): 50
    The role and metabolic adaptations of neutrophils in premetastatic niches.
    Enli Chen, Jing Yu.
      It has been found that tumor cells create microenvironments in distant organs that promote their survival and growth in advance of their arrival. These predetermined microenvironments are referred to as "pre-metastatic niches". Increasing attention is being paid to neutrophils' role in forming the pre-metastatic niche. As major components of the pre-metastatic niche, tumor-associated neutrophils (TANs) play an important role in the formation of the pre-metastatic niche through communication with multiple growth factors, chemokines, inflammatory factors, and other immune cells, which together create a pre-metastatic niche well suited for tumor cell seeding and growth. However, how TANs modulate their metabolism to survive and exert their functions in the process of metastasis remains largely to be discovered. Accordingly, the objective of this review is to assess the role that neutrophils play in the formation of pre-metastatic niche and to explore the metabolism alteration of neutrophils in cancer metastasis. A better understanding of the role of TANs in pre-metastatic niche will help us discover new mechanisms of metastasis and develop new therapies targeting TANs.
    Keywords:  Cancer; Metabolism; Metastasis; Neutrophil; Pre-metastatic niches
    DOI:  https://doi.org/10.1186/s40364-023-00493-6
  3. JCI Insight. 2023 May 11. pii: e160345. [Epub ahead of print]
    T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade.
    Kyungho Lee, Elizabeth A Thompson, Sepideh Gharaie, Chirag H Patel, Johanna T Kurzhagen, Phillip M Pierorazio, Lois J Arend, Ajit G Thomas, Sanjeev Noel, Barbara S Slusher, Hamid Rabb.
      T cells play an important role in acute kidney injury (AKI). Metabolic programming of T cells regulates their function, is a rapidly emerging field, and is unknown in AKI. We induced ischemic AKI in C57B6 mice and collected kidneys and spleens at multiple time points. T cells were isolated and analyzed by an immune-metabolic assay. Unbiased machine learning analyses identified a distinct T cell subset with reduced VDAC1 and mTOR expression in post-AKI kidneys. Ischemic kidneys showed higher expression of trimethylation of histone H3 lysine 27 (H3K27Me3) and glutaminase. Splenic T cells from post-AKI mice had higher expression of GLUT1, hexokinase II, and CPT1a. Human nonischemic and ischemic kidney tissue displayed similar findings to mouse kidneys. Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist JHU083, effects on AKI were evaluated. JHU083 attenuated renal injury and reduced T cell activation and proliferation in ischemic and nephrotoxic AKI, whereas T cell-deficient mice were not protected by glutamine blockade. In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach.
    Keywords:  Immunology; Nephrology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.160345
  4. Nat Commun. 2023 May 10. 14(1): 2692
    Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.
    Chenglong Sun, Anqiang Wang, Yanhe Zhou, Panpan Chen, Xiangyi Wang, Jianpeng Huang, Jiamin Gao, Xiao Wang, Liebo Shu, Jiawei Lu, Wentao Dai, Zhaode Bu, Jiafu Ji, Jiuming He.
      Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated "tumor-normal interface" region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.
    DOI:  https://doi.org/10.1038/s41467-023-38360-5
  5. Nat Cancer. 2023 May 11.
    GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.
    Dionysios C Watson, Defne Bayik, Simon Storevik, Shannon Sherwin Moreino, Samuel A Sprowls, Jianhua Han, Mina Thue Augustsson, Adam Lauko, Palavalasa Sravya, Gro Vatne Røsland, Katie Troike, Karl Johan Tronstad, Sabrina Wang, Katharina Sarnow, Kristen Kay, Taral R Lunavat, Daniel J Silver, Sahil Dayal, Justin Vareecal Joseph, Erin Mulkearns-Hubert, Lars Andreas Rømo Ystaas, Gauravi Deshpande, Joris Guyon, Yadi Zhou, Capucine R Magaut, Juliana Seder, Laura Neises, Sarah E Williford, Johannes Meiser, Andrew J Scott, Peter Sajjakulnukit, Jason A Mears, Rolf Bjerkvig, Abhishek Chakraborty, Thomas Daubon, Feixiong Cheng, Costas A Lyssiotis, Daniel R Wahl, Anita B Hjelmeland, Jubayer A Hossain, Hrvoje Miletic, Justin D Lathia.
      The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.
    DOI:  https://doi.org/10.1038/s43018-023-00556-5
  6. Endocrinology. 2023 May 12. pii: bqad073. [Epub ahead of print]
    NAD + Metabolism Generates a Metabolic Vulnerability in Endocrine-Resistant Metastatic Breast Tumors in Females.
    Ayca Nazli Mogol, Qianying Zuo, Jin Young Yoo, Alanna Zoe Kaminsky, Ozan Berk Imir, Yosef Landesman, Christopher J Walker, Zeynep Madak Erdogan.
      Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30%-40% of patients with ER+ breast cancer still experiences recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified NAMPT, an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with Fulv. We tested whether the blockade of NAD+ production via inhibition of nicotinamide phosphoribosyltransferase (NAMPT) synergizes with standard-of-care therapies for ER+ metastatic breast cancer in vitro and in vivo. A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and fulvestrant (Fulv) works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibitor in combination with Fulv reversed the expression of gene sets associated with more aggressive tumor phenotype, and metabolomics analysis showed that NAMPT inhibition reduced the abundance of metabolites associated with several key tumor metabolic pathways. Targeting metabolic adaptations in endocrine-resistant metastatic breast cancer is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ERα-NAMPT cross-talk in metastatic breast cancer and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of metastatic breast cancer treatment.
    Keywords:  NAMPT; estrogen receptor; fulvestrant; metabolism; metastatic breast cancer
    DOI:  https://doi.org/10.1210/endocr/bqad073
  7. Nat Commun. 2023 05 06. 14(1): 2634
    MetaTiME integrates single-cell gene expression to characterize the meta-components of the tumor immune microenvironment.
    Yi Zhang, Guanjue Xiang, Alva Yijia Jiang, Allen Lynch, Zexian Zeng, Chenfei Wang, Wubing Zhang, Jingyu Fan, Jiajinlong Kang, Shengqing Stan Gu, Changxin Wan, Boning Zhang, X Shirley Liu, Myles Brown, Clifford A Meyer.
      Recent advances in single-cell RNA sequencing have shown heterogeneous cell types and gene expression states in the non-cancerous cells in tumors. The integration of multiple scRNA-seq datasets across tumors can indicate common cell types and states in the tumor microenvironment (TME). We develop a data driven framework, MetaTiME, to overcome the limitations in resolution and consistency that result from manual labelling using known gene markers. Using millions of TME single cells, MetaTiME learns meta-components that encode independent components of gene expression observed across cancer types. The meta-components are biologically interpretable as cell types, cell states, and signaling activities. By projecting onto the MetaTiME space, we provide a tool to annotate cell states and signature continuums for TME scRNA-seq data. Leveraging epigenetics data, MetaTiME reveals critical transcriptional regulators for the cell states. Overall, MetaTiME learns data-driven meta-components that depict cellular states and gene regulators for tumor immunity and cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-023-38333-8
  8. Cancer Lett. 2023 May 05. pii: S0304-3835(23)00159-3. [Epub ahead of print] 216208
    Myeloid-derived suppressor cells deficient in cholesterol biosynthesis promote tumor immune evasion.
    Yu Chen, Yanquan Xu, Huakan Zhao, Yu Zhou, Jiangang Zhang, Juan Lei, Lei Wu, Mingyue Zhou, Jingchun Wang, Shuai Yang, Xiao Zhang, Guifang Yan, Yongsheng Li.
      Cancer immunotherapy targeting myeloid-derived suppressor cells (MDSCs) is one of the most promising anticancer strategies. Metabolic reprogramming is vital for MDSC activation, however, the regulatory mechanisms of cholesterol metabolic reprogramming in MDSCs remains largely unexplored. Using the receptor-interacting protein kinase 3 (RIPK3)-deficient MDSC model, a previously established tumor-infiltrating MDSC-like model, we found that the cholesterol accumulation was significantly decreased in these cells. Moreover, the phosphorylated AKT-mTORC1 signaling was reduced, and downstream SREBP2-HMGCR-mediated cholesterol synthesis was blunted. Interestingly, cholesterol deficiency profoundly elevated the immunosuppressive activity of MDSCs. Mechanistically, cholesterol elimination induced nuclear accumulation of LXRβ, thereby promoting LXRβ-RXRα heterodimer binding of a novel composite element in the promoter of Arg1. Furthermore, itraconazole enhanced the immunosuppressive activity of MDSCs to boost tumor growth by suppressing the RIPK3-AKT-mTORC1 pathway and impeding cholesterol synthesis. Our findings demonstrate that RIPK3 deficiency leads to cholesterol abrogation in MDSCs, which facilitates tumor-infiltrating MDSC activation, and highlight the therapeutic potential of targeting cholesterol synthesis to overcome tumor immune evasion.
    Keywords:  Cholesterol; Metabolism; Myeloid-derived suppressor cells; Tumor immunity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216208
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