bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–02–12
eight papers selected by
Linda Chan, Cleveland Clinic
  1. Control of immune cell function by the unfolded protein response.
  2. Oncogenic IDH1 Mutation Imparts Therapeutically Targetable Metabolic Dysfunction in Multiple Tumor Types.
  3. Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1.
  4. Drugging a metabolic vulnerability in glioblastoma.
  5. Metabolic flexibility in ccRCC.
  6. Metabolic individuality: Limitations, challenges, and potential for clinical utility.
  7. Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.
  8. Exploring the expressiveness of abstract metabolic networks.
  1. Nat Rev Immunol. 2023 Feb 08.
    Control of immune cell function by the unfolded protein response.
    Giusy Di Conza, Ping-Chih Ho, Juan R Cubillos-Ruiz, Stanley Ching-Cheng Huang.
      Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes orchestrated by the endoplasmic reticulum. Importantly, diverse extracellular and intracellular conditions can compromise the protein-handling capacity of this organelle, inducing a state of 'endoplasmic reticulum stress' that activates the unfolded protein response (UPR). Emerging evidence shows that physiological or pathological activation of the UPR can have effects on immune cell survival, metabolism, function and fate. In this Review, we discuss the canonical role of the adaptive UPR in immune cells and how dysregulation of this pathway in leukocytes contributes to diverse pathologies such as cancer, autoimmunity and metabolic disorders. Furthermore, we provide an overview as to how pharmacological approaches that modulate the UPR could be harnessed to control or activate immune cell function in disease.
    DOI:  https://doi.org/10.1038/s41577-023-00838-0
  2. Cancer Discov. 2023 Feb 06. 13(2): 266-268
    Oncogenic IDH1 Mutation Imparts Therapeutically Targetable Metabolic Dysfunction in Multiple Tumor Types.
    Troy M Robinson, Ross L Levine.
       SUMMARY: In this issue of Cancer Discovery, Thomas and colleagues leverage mass spectrometry metabolomics, stable isotope labeling, and functional studies to explore metabolic vulnerabilities in cancers harboring mutations in isocitrate dehydrogenase (IDH). The authors present compelling data to support the claim that dysregulated lipid synthesis underpins a synthetic lethal target in cancers with IDH1, but not IDH2, mutations. See related article by Thomas et al., p. 496 (9).
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1325
  3. Oncogene. 2023 Feb 09.
    Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1.
    Linmeng Han, Chunyu Zhang, Danni Wang, Jiaqi Zhang, Qiqi Tang, Mulin Jun Li, Michael N Sack, Lingdi Wang, Lu Zhu.
      Metabolic reprogram is crucial to support cancer cell growth and movement as well as determine cell fate. Mitochondrial protein acetylation regulates mitochondrial metabolism, which is relevant to cancer cell migration and invasion. The functional role of mitochondrial protein acetylation on cancer cell migration remains unclear. General control of amino acid synthesis 5 like-1(GCN5L1), as the regulator of mitochondrial protein acetylation, functions on metabolic reprogramming in mouse livers. In this study, we find that GCN5L1 expression is significantly decreased in metastatic HCC tissues. Loss of GCN5L1 promotes reactive oxygen species (ROS) generation through enhanced fatty acid oxidation (FAO), followed by activation of cellular ERK and DRP1 to promote mitochondrial fission and epithelia to mesenchymal transition (EMT) to boost cell migration. Moreover, palmitate and carnitine-stimulated FAO promotes mitochondrial fission and EMT gene expression to activate HCC cell migration. On the other hand, increased cellular acetyl-CoA level, the product of FAO, enhances HCC cell migration. Taken together, our finding uncovers the metastasis suppressor role as well as the underlying mechanism of GCN5L1 in HCC and also provides evidence of FAO retrograde control of HCC metastasis.
    DOI:  https://doi.org/10.1038/s41388-023-02621-w
  4. Nat Rev Drug Discov. 2023 Feb 07.
    Drugging a metabolic vulnerability in glioblastoma.
    Katie Kingwell.
      
    DOI:  https://doi.org/10.1038/d41573-023-00020-0
  5. Nat Rev Urol. 2023 Feb 10.
    Metabolic flexibility in ccRCC.
    Louise Stone.
      
    DOI:  https://doi.org/10.1038/s41585-023-00734-1
  6. Cell Metab. 2023 Feb 07. pii: S1550-4131(23)00007-4. [Epub ahead of print]35(2): 233-235
    Metabolic individuality: Limitations, challenges, and potential for clinical utility.
    Sarah H Elsea, Jennifer E Posey.
      In Nature Medicine, Surendran and colleagues recently reported the analysis of human plasma metabolomic data for 913 metabolites in ∼20,000 individuals, identifying 2,599 metabolite-genetic variant associations and >400 metabolite signatures comprised of jointly regulated metabolites. This extensive atlas of variant-metabolite relationships reveals novel genomic mechanisms driving metabolic phenotypes.
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.007
  7. Leukemia. 2023 Feb 04.
    Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia.
    Clement Larrue, Sarah Mouche, Shan Lin, Federico Simonetta, Nastassja K Scheidegger, Laury Poulain, Rudy Birsen, Jean-Emmanuel Sarry, Kimberly Stegmaier, Jerome Tamburini.
      Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.
    DOI:  https://doi.org/10.1038/s41375-023-01835-x
  8. PLoS One. 2023 ;18(2): e0281047
    Exploring the expressiveness of abstract metabolic networks.
    Irene García, Bessem Chouaia, Mercè Llabrés, Marta Simeoni.
      Metabolism is characterised by chemical reactions linked to each other, creating a complex network structure. The whole metabolic network is divided into pathways of chemical reactions, such that every pathway is a metabolic function. A simplified representation of metabolism, which we call an abstract metabolic network, is a graph in which metabolic pathways are nodes and there is an edge between two nodes if their corresponding pathways share one or more compounds. The abstract metabolic network of a given organism results in a small network that requires low computational power to be analysed and makes it a suitable model to perform a large-scale comparison of organisms' metabolism. To explore the potentials and limits of such a basic representation, we considered a comprehensive set of KEGG organisms, represented through their abstract metabolic network. We performed pairwise comparisons using graph kernel methods and analyse the results through exploratory data analysis and machine learning techniques. The results show that abstract metabolic networks discriminate macro evolutionary events, indicating that they are expressive enough to capture key steps in metabolism evolution.
    DOI:  https://doi.org/10.1371/journal.pone.0281047
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