bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2024–03–17
seven papers selected by
Alex Muir, University of Chicago
  1. Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia.
  2. 13 C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
  3. Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
  4. Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
  5. Advancing glioblastoma treatment by targeting metabolism.
  6. Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.
  7. Molecular, Metabolic, and Subcellular Mapping of the Tumor Immune Microenvironment via 3D Targeted and Non-Targeted Multiplex Multi-Omics Analyses.
  1. EMBO J. 2024 Mar 14.
    Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia.
    Fiona Grimm, Agustín Asuaje, Aakriti Jain, Mariana Silva Dos Santos, Jens Kleinjung, Patrícia M Nunes, Stefanie Gehrig, Louise Fets, Salihanur Darici, James I MacRae, Dimitrios Anastasiou.
      Adaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia-inducible factor 1α (HIF1α) and are necessary for cancer cell survival. However, the mechanisms that enable cancer cells to adapt in early hypoxia, before the HIF1α-mediated transcription programme is fully established, remain poorly understood. Here we show in human breast cancer cells, that within 3 h of hypoxia exposure, glycolytic flux increases in a HIF1α-independent manner but is limited by NAD+ availability. Glycolytic ATP maintenance and cell survival in early hypoxia rely on reserve lactate dehydrogenase A capacity as well as the activity of glutamate-oxoglutarate transaminase 1 (GOT1), an enzyme that fuels malate dehydrogenase 1 (MDH1)-derived NAD+. In addition, GOT1 maintains low α-ketoglutarate levels, thereby limiting prolyl hydroxylase activity to promote HIF1α stabilisation in early hypoxia and enable robust HIF1α target gene expression in later hypoxia. Our findings reveal that, in normoxia, multiple enzyme systems maintain cells in a primed state ready to support increased glycolysis and HIF1α stabilisation upon oxygen limitation, until other adaptive processes that require more time are fully established.
    Keywords:  Glycolysis; HIF1α; Hypoxia; Metabolism; α-Ketoglutarate
    DOI:  https://doi.org/10.1038/s44318-024-00065-w
  2. bioRxiv. 2024 Feb 28. pii: 2023.08.18.553810. [Epub ahead of print]
    13 C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
    Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Shahraz Mohammed, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.
      Metabolism has emerged as a key factor in homeostasis and disease including cancer. Yet, little is known about the heterogeneity of metabolic activity of cancer cells due to the lack of tools to directly probe it. Here, we present a novel method, 13 C-SpaceM for spatial single-cell isotope tracing of glucose-dependent de novo lipogenesis. The method combines imaging mass spectrometry for spatially-resolved detection of 13 C 6 -glucose-derived 13 C label incorporated into esterified fatty acids with microscopy and computational methods for data integration and analysis. We validated 13 C-SpaceM on a spatially-heterogeneous normoxia-hypoxia model of liver cancer cells. Investigating cultured cells, we revealed single-cell heterogeneity of lipogenic acetyl-CoA pool labelling degree upon ACLY knockdown that is hidden in the bulk analysis and its effect on synthesis of individual fatty acids. Next, we adapted 13 C-SpaceM to analyze tissue sections of mice harboring isocitrate dehydrogenase (IDH)-mutant gliomas. We found a strong induction of de novo fatty acid synthesis in the tumor tissue compared to the surrounding brain. Comparison of fatty acid isotopologue patterns revealed elevated uptake of mono-unsaturated and essential fatty acids in the tumor. Furthermore, our analysis uncovered substantial spatial heterogeneity in the labelling of the lipogenic acetyl-CoA pool indicative of metabolic reprogramming during microenvironmental adaptation. Overall, 13 C-SpaceM enables novel ways for spatial probing of metabolic activity at the single cell level. Additionally, this methodology provides unprecedented insight into fatty acid uptake, synthesis and modification in normal and cancerous tissues.
    DOI:  https://doi.org/10.1101/2023.08.18.553810
  3. Nat Commun. 2024 Mar 11. 15(1): 2203
    Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
    Luca Simula, Mattia Fumagalli, Lene Vimeux, Irena Rajnpreht, Philippe Icard, Gary Birsen, Dongjie An, Frédéric Pendino, Adrien Rouault, Nadège Bercovici, Diane Damotte, Audrey Lupo-Mansuet, Marco Alifano, Marie-Clotilde Alves-Guerra, Emmanuel Donnadieu.
      The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.
    DOI:  https://doi.org/10.1038/s41467-024-46377-7
  4. R Soc Open Sci. 2024 Mar;11(3): 231574
    Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
    Mudita Shukla, Rupa Bhowmick, Piyali Ganguli, Ram Rup Sarkar.
      Tumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towards a pro-inflammatory state and conquer tumour dominance. This study proposes immunomodulatory mechanisms based on metabolic reprogramming and employs the regulatory flux balance analysis modelling approach, which integrates signalling, metabolism and regulatory processes. For the first time, a comprehensive system-level model is constructed to capture signalling and metabolic cross-talks during tumour-immune interaction and regulatory constraints are incorporated by considering the time lag between them. The model analysis identifies novel features to enhance the immune response while suppressing tumour activity. Particularly, altering the exchange of succinate and oxaloacetate between glioma and macrophage enhances the pro-inflammatory response of immune cells. Inhibition of glutamate uptake in T-cells disrupts the antioxidant mechanism of glioma and reprograms metabolism. Metabolic reprogramming through adenosine monophosphate (AMP)-activated protein kinase (AMPK), coupled with glutamate uptake inhibition, was identified as the most impactful combination to restore T-cell function. A comprehensive understanding of metabolism and gene regulation represents a favourable approach to promote immune cell recovery from tumour dominance.
    Keywords:  metabolic reprogramming; signalling-metabolic cross-talks; system modelling; tumour–immune interaction
    DOI:  https://doi.org/10.1098/rsos.231574
  5. Neoplasia. 2024 Mar 12. pii: S1476-5586(24)00022-8. [Epub ahead of print]51 100985
    Advancing glioblastoma treatment by targeting metabolism.
    Jinyi Zhao, Xuemei Ma, Peixian Gao, Xueqi Han, Pengxiang Zhao, Fei Xie, Mengyu Liu.
      Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.
    Keywords:  Glioblastoma; Metabolism; Signaling pathway; Therapy
    DOI:  https://doi.org/10.1016/j.neo.2024.100985
  6. Sci Adv. 2024 Mar 15. 10(11): eadm8600
    Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.
    Elton T Montrazi, Keren Sasson, Lilach Agemy, Avigdor Scherz, Lucio Frydman.
      Cancer diagnosis by metabolic MRI proposes to follow the fate of glycolytic precursors such as pyruvate or glucose, and their in vivo conversion into lactate. This study compares the 2H MRI outlooks afforded by these metabolites when targeting a pancreatic cancer model. Exogenously injected [3,3',3″-2H3]-pyruvate was visible only briefly; it generated a deuterated lactate signal throughout the body that faded after ~5 min, showing a minor concentration bias at the rims of the tumors. [6,6'-2H2]-glucose by contrast originated a lactate signal that localized clearly within the tumors, persisting for over an hour. Investigations alternating deuterated and nondeuterated glucose injections revealed correlations between the lactate generation and the glucose available at the tumor, evidencing a continuous and avid glucose consumption generating well-localized lactate signatures as driven by the Warburg effect. This is by contrast to the transient and more promiscuous pyruvate-to-lactate transformation, which seemed subject to transporter and kinetics effects. The consequences of these observations within metabolic MRI are briefly discussed.
    DOI:  https://doi.org/10.1126/sciadv.adm8600
  7. Cancers (Basel). 2024 Feb 20. pii: 846. [Epub ahead of print]16(5):
    Molecular, Metabolic, and Subcellular Mapping of the Tumor Immune Microenvironment via 3D Targeted and Non-Targeted Multiplex Multi-Omics Analyses.
    Sammy Ferri-Borgogno, Jared K Burks, Erin H Seeley, Trevor D McKee, Danielle L Stolley, Akshay V Basi, Javier A Gomez, Basant T Gamal, Shamini Ayyadhury, Barrett C Lawson, Melinda S Yates, Michael J Birrer, Karen H Lu, Samuel C Mok.
      Most platforms used for the molecular reconstruction of the tumor-immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell-cell or cell-extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) and targeted seqIF (IHC proteomics). The spatially resolved imaging data in a two- and three-dimensional space demonstrated various cellular neighborhoods in both samples. The collection of spatially resolved analytes in a voxel (3D pixel) across serial sections of the tissue was also demonstrated. Data collected from this analytical pipeline were used to construct spatial 3D maps with single-cell resolution, which revealed cell identity, activation, and energized status. These maps will provide not only insights into the molecular basis of spatial cell heterogeneity in the TIME, but also novel predictive biomarkers and therapeutic targets, which can improve patient survival rates.
    Keywords:  3D spatial multi-omics; Stereo-seq; atypical endometrial hyperplasia; mass spectrometry imaging; microbiome; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16050846
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