bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–11–24
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.
  2. The importance of growth differentiation factor 15 and interleukin 6 serum levels in inflammatory bowel diseases.
  3. The role of hypoxic microenvironment in autoimmune diseases.
  4. The influence of endothelial metabolic reprogramming on the tumor microenvironment.
  5. Role of Arginine and its Metabolism in TGF-β-Induced Activation of Lung Fibroblasts.
  6. Cancer cachexia: multilevel metabolic dysfunction.
  7. Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin.
  8. Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.
  1. bioRxiv. 2024 Oct 28. pii: 2024.10.23.619897. [Epub ahead of print]
    Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.
    Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Maria E Salvatierra, Wei Lui, Khaja Khan, Luisa Maris Solis Soto, Ignacio Wistuba, John D Minna, Kathryn A O'Donnell.
      The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5' UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.
    Statement of Significance: This study uncovers a novel mechanism for the coordinated translational regulation of the PD-L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.
    DOI:  https://doi.org/10.1101/2024.10.23.619897
  2. J Physiol Biochem. 2024 Nov 19.
    The importance of growth differentiation factor 15 and interleukin 6 serum levels in inflammatory bowel diseases.
    Evgenia Koureta, Pantelis Karatzas, Panagiotis N Kanellopoulos, Angeliki Papapanagiotou, Vasileios Lekakis, Giorgos Bamias, George Karamanolis, Jiannis Vlachogiannakos, Athanasios G Papavassiliou, George V Papatheodoridis.
      There are only scarce recent reports about the role of growth differentiation factor 15 (GDF-15) and some more data about interleukin-6 (IL-6) in inflammatory bowel diseases (IBD). We assessed GDF-15 and IL-6 serum levels in patients with IBD and associations with their characteristics. We included 122 and 71 stored samples from patients with Crohn's disease (CD) and ulcerative colitis (UC), respectively, and regular follow-up and 44 samples from healthy controls. Data regarding epidemiologic and disease characteristics were recorded. In CD, both GDF-15 and IL-6 levels were higher in active disease or all patients than controls (P ≤ 0.020) as well as patients with elevated CRP (P ≤ 0.008), endoscopically active disease (P ≤ 0.017), age ≥ 40 years (P ≤ 0.005) and active smokers (P ≤ 0.050) and were positively correlated with hospitalization numbers (P ≤ 0.019). GDF-15 levels were also positively correlated with flares within year-1 (P < 0.001). In UC, both GDF-15 and IL-6 levels were higher in clinically active or all patients than controls (P < 0.001), but they shared no other association with patient characteristics except for positive correlation with CRP. Only IL-6 levels were higher in active than inactive UC either clinically (P = 0.047) or endoscopically (P < 0.001) and were positively correlated with stool calprotectin (P = 0.021). GDF-15 was positively correlated to IL-6 levels only in UC (rs=0.591, P < 0.001) but not in CD. In conclusion, in CD, GDF-15 and IL-6 levels could constitute indexes of activity and even offer a prognostic index of disease progression. In UC, IL-6 could also represent an activity index, but the role of GDF-15 needs further evaluation.
    Keywords:  Crohn’s disease; Growth differentiation factor-15; Interleukin-6; Macrophage inhibitory cytokine-1; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s13105-024-01057-4
  3. Front Immunol. 2024 ;15 1435306
    The role of hypoxic microenvironment in autoimmune diseases.
    Xun Gong, Su-Yin Yang, Zhen-Yu Wang, Min Tang.
      The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention.
    Keywords:  autoimmune diseases; hypoxia-inducible factor-1; hypoxic microenvironment; immune cells; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fimmu.2024.1435306
  4. Oncogene. 2024 Nov 20.
    The influence of endothelial metabolic reprogramming on the tumor microenvironment.
    Kelby Kane, Deanna Edwards, Jin Chen.
      Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41388-024-03228-5
  5. bioRxiv. 2024 Nov 01. pii: 2024.11.01.618293. [Epub ahead of print]
    Role of Arginine and its Metabolism in TGF-β-Induced Activation of Lung Fibroblasts.
    Robert B Hamanaka, Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Hardik Shah, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Takugo Cho, Gökhan M Mutlu.
      Arginine is a conditionally essential amino acid with known roles in protein production, nitric oxide synthesis, biosynthesis of proline and polyamines, and regulation of intracellular signaling pathways. Arginine biosynthesis and catabolism have been linked to TGF-β-induced activation of fibroblasts in the context of pulmonary fibrosis; however, a thorough study on the metabolic and signaling roles of arginine in the process of fibroblast activation has not been conducted. Here, we used metabolic dropouts and labeling strategies to determine how activated fibroblasts utilize arginine. We found that arginine limitation leads to activation of GCN2 while inhibiting TGF-β-induced mTORC1 activation and collagen protein production. Extracellular citrulline could rescue the effect of arginine deprivation in an ASS1-dependent manner. Using metabolic tracers of arginine and its precursors, we found little evidence of arginine synthesis or catabolism in lung fibroblasts treated with TGF-β. Extracellular ornithine or glutamine were the primary sources of ornithine and polyamines, not arginine. Our findings suggest that the major role for arginine in lung fibroblasts is for charging of arginyl-tRNAs and for promotion of mTOR signaling.
    Keywords:  Arginine; Fibroblast; Metabolism; Pulmonary Fibrosis
    DOI:  https://doi.org/10.1101/2024.11.01.618293
  6. Nat Metab. 2024 Nov 22.
    Cancer cachexia: multilevel metabolic dysfunction.
    Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig.
      Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or 'wasting' of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches.
    DOI:  https://doi.org/10.1038/s42255-024-01167-9
  7. J Natl Cancer Inst. 2024 Nov 19. pii: djae295. [Epub ahead of print]
    Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin.
    Randall J Smith, Robert Zollo, Sukumar Kalvapudi, Yeshwanth Vedire, Akhil Goud Pachimatla, Cara Petrucci, Garrison Shaller, Deschana Washington, Vethanayagam Rr, Stephanie N Sass, Aravind Srinivasan, Eric Kannisto, Sawyer Bawek, Prantesh Jain, Spencer Rosario, Joseph Barbi, Sai Yendamuri.
       BACKGROUND: Pre-clinical cancer studies ascribe promising anticancer properties to metformin. Yet, clinical findings vary, casting uncertainty on its therapeutic value for non-small cell lung cancer (NSCLC) patients. We hypothesized that metformin could benefit obese and overweight patients with NSCLC.
    METHODS: We retrospectively analyzed two clinical cohorts and employed complementary mouse models to test our hypothesis. One cohort included NSCLC patients with overweight BMI (≥25, n = 511) and non-overweight BMI (<25, n = 232) who underwent lobectomy, evaluating metformin's impact on clinical outcomes. Another cohort examined metformin's effect on progression-free survival (PFS) after immune checkpoint inhibitors (ICI) in overweight (n = 284) vs non-overweight (n = 184) NSCLC patients. Metformin's effects on tumor progression, antitumor immunity, and ICI response in obese and normal-weight mice were assessed with lung cancer models.
    RESULTS: Metformin is associated with increased recurrence-free survival in overweight patients (HR = 0.47 [95%CI = 0.24-0.94], p = .035) after lobectomy. It also corrected accelerated tumor growth in diet-induced obese mouse models in a lymphocyte-specific manner while reversing several mechanisms of immune suppression potentiated by obesity. PD-1 blockade coupled with metformin was more effective at limiting tumor burden in obese mice and correlated with PFS only in overweight patients on immunotherapy (HR = 0.60, [95%CI = 0.39-0.93], p = .024).
    CONCLUSIONS: Metformin may improve lung cancer-specific clinical outcomes in obese and overweight lung cancer patients and enhance immunotherapy efficacy in this growing population as well. This work identifies obesity as a potential predictive biomarker of metformin's anticancer and immunotherapy-enhancing properties in lung cancer while shedding light on the underlying immunological phenomena.
    DOI:  https://doi.org/10.1093/jnci/djae295
  8. Am J Respir Cell Mol Biol. 2024 Nov 18.
    Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.
    Nicholaus L DeCuzzi, Daniel Oberbauer, Kenneth J Chmiel, Michael Pargett, Justa M Ferguson, Devan Murphy, Marion Hardy, Abhineet Ram, Amir A Zeki, John G Albeck.
      Spatially coordinated ERK signaling events ("SPREADs") transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. To address these questions, we measured SPREAD activity with live-cell ERK biosensors in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial (pHBE) cells, in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Airway epithelial cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD). Type 1 pro-inflammatory cytokines significantly increased the frequency of SPREADs, which coincided with epithelial barrier breakdown in differentiated pHBE cells. Furthermore, SPREADs correlated with IL-6 peptide secretion and the appearance of localized clusters of phospho-STAT3 immunofluorescence. To probe the mechanism of SPREADs, cells were co-treated with pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) or metabolic modulators (insulin, 2-deoxyglucose). Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREAD occurrence, implying that pro-inflammatory cytokines and glucose metabolism modulate SPREADs in human airway epithelial cells via secreted EGFR and IL6R ligands. We conclude that spatiotemporal ERK signaling plays a role in barrier homeostasis and dysfunction during inflammation of the airway epithelium. This novel signaling mechanism could be exploited clinically to supplement corticosteroid treatment for asthma and COPD.
    Keywords:  forster resonance energy transfer (FRET); mitogen activated protein kinase (MAPK) , epidermal growth factor receptor (EGFR)
    DOI:  https://doi.org/10.1165/rcmb.2024-0256OC
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