bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–09–29
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
  2. Identification and characterization of human GDF15 knockouts.
  3. General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases.
  4. eIF2B localization and its regulation during the integrated stress response is cell-type specific.
  5. Research progress on the role of adipocyte exosomes in cancer progression.
  6. GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.
  7. Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective.
  8. Metabolic reprogramming of macrophages in cancer therapy.
  9. Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
  10. Lactate-Induced HBEGF Shedding and EGFR Activation: Paving the Way to a New Anticancer Therapeutic Opportunity.
  1. Cardiovasc Res. 2024 Sep 23. pii: cvae214. [Epub ahead of print]
    GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
    Minoru Takaoka, John A Tadross, Ali B A K Al-Hadithi, Xiaohui Zhao, Rocío Villena-Gutiérrez, Jasper Tromp, Shazia Absar, Marcus Au, James Harrison, Anthony P Coll, Stefan J Marciniak, Debra Rimmington, Eduardo Oliver, Borja Ibáñez, Adriaan A Voors, Stephen O'Rahilly, Ziad Mallat, Jane C Goodall.
       AIMS: Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A.
    METHODS AND RESULTS: Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure.
    CONCLUSION: Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
    Keywords:  GDF15; Heart Failure; Integrated stress response; PPP1R15A; cachexia
    DOI:  https://doi.org/10.1093/cvr/cvae214
  2. Nat Metab. 2024 Sep 26.
    Identification and characterization of human GDF15 knockouts.
    Allan M Gurtan, Shareef Khalid, Christopher Koch, Maleeha Zaman Khan, Lindsey B Lamarche, Igor Splawski, Elizabeth Dolan, Ana M Carrion, Richard Zessis, Matthew E Clement, Zhiping Chen, Loren D Lindsley, Yu-Hsin Chiu, Ryan S Streeper, Daniel P Denning, Allison B Goldfine, Brian Doyon, Ali Abbasi, Jennifer L Harrow, Kazuhisa Tsunoyama, Makoto Asaumi, Ikuyo Kou, Alan R Shuldiner, Juan L Rodriguez-Flores, Asif Rasheed, Muhammad Jahanzaib, Muhammad Rehan Mian, Muhammad Bilal Liaqat, Syed Shahzaib Raza, Riffat Sultana, Anjum Jalal, Muhammad Hamid Saeed, Shahid Abbas, Fazal Rehman Memon, Mohammad Ishaq, John E Dominy, Danish Saleheen.
      Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous ('knockouts') and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.
    DOI:  https://doi.org/10.1038/s42255-024-01135-3
  3. Front Aging. 2024 ;5 1447370
    General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases.
    Ozlem Altintas, Michael R MacArthur.
      The function of General Control Nonderepressible 2 (GCN2), an evolutionary-conserved component of the integrated stress response (ISR), has been well-documented across organisms from yeast to mammals. Recently GCN2 has also gained attention for its role in health and disease states. In this review, we provide a brief overview of GCN2, including its structure, activation mechanisms and interacting partners, and explore its potential significance as a therapeutic target in various age-related diseases including neurodegeneration, inflammatory disorders and cancer. Finally, we summarize the barriers to effectively targeting GCN2 for the treatment of disease and to promote a healthier aging process.
    Keywords:  GCN2; ISR; aging; amino acids; cancer; geroprotection; gerotherapeutic
    DOI:  https://doi.org/10.3389/fragi.2024.1447370
  4. iScience. 2024 Sep 20. 27(9): 110851
    eIF2B localization and its regulation during the integrated stress response is cell-type specific.
    Filipe M Hanson, Madalena I Ribeiro de Oliveira, Alison K Cross, K Elizabeth Allen, Susan G Campbell.
      Eukaryotic initiation factor 2B (eIF2B) controls translation initiation by recycling inactive eIF2-GDP to active eIF2-GTP. Under cellular stress, the integrated stress response (ISR) is activated inhibiting eIF2B activity resulting in the translation attenuation and reprogramming of gene expression to overcome the stress. The ISR can dictate cell fate wherein chronic activation has pathological outcomes. Vanishing white matter disease (VWMD) is a chronic ISR-related disorder with mutations in eIF2B targeting astrocyte and oligodendrocyte cells. Regulation of eIF2B localization (eIF2B bodies) has been implicated in the ISR. We present evidence that neuronal and glial cell types possess distinct patterns of eIF2B bodies which change in a manner correlating to acute and chronic ISR activation. We also demonstrate that while neural and glial cell types respond similarly to the acute induction of the ISR a chronic ISR exerts cell-type specific differences. These findings provide key insights into neural cell responses and adaptation to cellular stress.
    Keywords:  Biological sciences; Cell; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110851
  5. Oncol Res. 2024 ;32(10): 1649-1660
    Research progress on the role of adipocyte exosomes in cancer progression.
    Yun Wang, Xiaojiang Li, Dalong Liu, Zhifeng Wang, Jichen Xia, Lijun Wang, Xudong Zhang.
      Exosomes, minute vesicles ubiquitously released by diverse cell types, serve as critical mediators in intercellular communication. Their pathophysiological relevance, especially in malignancies, has garnered significant attention. A meticulous exploration of the exosomal impact on cancer development has unveiled avenues for innovative and clinically valuable techniques. The cargo conveyed by exosomes exerts transformative effects on both local and distant microenvironments, thereby influencing a broad spectrum of biological responses in recipient cells. These membrane-bound extracellular vesicles (EVs) play a pivotal role in delivering bioactive molecules among cells and organs. Cellular and biological processes in recipient cells, ranging from stromal cell reprogramming to immunological responses, extracellular matrix formation, and modulation of cancer cell activation, expansion, and metastasis, are subject to exosome-mediated cell-to-cell communication. Moreover, exosomes have been implicated in endowing cancer cells with resistance to treatment. Extensive research has explored the potential of exosomes as therapeutic targets and diagnostic indicators. This comprehensive review seeks to provide an in-depth understanding of the pivotal components and roles of exosomes in tumorigenesis, growth, progression, and therapeutic responses. The insights into the multifaceted involvement of exosomes in malignant cancers are essential for the scientific community, fostering the development of novel therapeutic and diagnostic strategies in the relentless pursuit of cancer.
    Keywords:  Adipose tissue; Exosomes; Extracellular vesicles; Obesity; Tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2024.043482
  6. JCI Insight. 2024 Sep 24. pii: e177926. [Epub ahead of print]
    GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.
    Maggie M Zhu, Jingbo Dai, Zhiyu Dai, Yi Peng, You-Yang Zhao.
      Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding GCN2, General control nonderepressibe 2 kinase) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely (approximately one percent) in PAH patients. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and PAH patients. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor PH but inhibited hypoxia-induced PH. RNA sequencing analysis suggested Endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss of function mutations.
    Keywords:  Cardiovascular disease; Endothelial cells; Protein kinases; Vascular biology
    DOI:  https://doi.org/10.1172/jci.insight.177926
  7. FEBS J. 2024 Sep 22.
    Harnessing nucleotide metabolism and immunity in cancer: a tumour microenvironment perspective.
    Hadil Sulieman, Alexandra Emerson, Peter M Wilson, Karl A Mulligan, Robert D Ladner, Melissa J LaBonte.
      The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM-targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established 'one size fits all' approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments.
    Keywords:  cancer immunology; immune checkpoint inhibitors; immunometabolism; metabolic therapies; nucleotide metabolism; purine metabolism; pyrimidine synthesis; therapeutic modulation; tumour microenvironment
    DOI:  https://doi.org/10.1111/febs.17278
  8. Trends Endocrinol Metab. 2024 Sep 19. pii: S1043-2760(24)00244-3. [Epub ahead of print]
    Metabolic reprogramming of macrophages in cancer therapy.
    Xudong Wang, Shaolong Zhang, Dixuan Xue, Dante Neculai, Jin Zhang.
      Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.
    Keywords:  cancer therapy; macrophage; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tem.2024.08.009
  9. Nat Commun. 2024 Sep 27. 15(1): 8301
    Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis.
    Katherine Labbé, Lauren LeBon, Bryan King, Ngoc Vu, Emily H Stoops, Nina Ly, Austin E Y T Lefebvre, Phillip Seitzer, Swathi Krishnan, Jin-Mi Heo, Bryson Bennett, Carmela Sidrauski.
      The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.
    DOI:  https://doi.org/10.1038/s41467-024-52538-5
  10. Cells. 2024 Sep 13. pii: 1533. [Epub ahead of print]13(18):
    Lactate-Induced HBEGF Shedding and EGFR Activation: Paving the Way to a New Anticancer Therapeutic Opportunity.
    Valentina Rossi, Alejandro Hochkoeppler, Marzia Govoni, Giuseppina Di Stefano.
      Cancer cells can release EGF-like peptides, acquiring the capacity of autocrine stimulation via EGFR-mediated signaling. One of these peptides (HBEGF) was found to be released from a membrane-bound precursor protein and is critically implicated in the proliferative potential of cancer cells. We observed that the increased lactate levels characterizing neoplastic tissues can induce the release of uPA, a protease promoting HBEGF shedding. This effect led to EGFR activation and increased ERK1/2 phosphorylation. Since EGFR-mediated signaling potentiates glycolytic metabolism, this phenomenon can induce a self-sustaining deleterious loop, favoring tumor growth. A well characterized HBEGF inhibitor is CRM197, a single-site variant of diphtheria toxin. We observed that, when administered individually, CRM197 did not trigger evident antineoplastic effects. However, its association with a uPA inhibitor caused dampening of EGFR-mediated signaling and apoptosis induction. Overall, our study highlights that the increased glycolytic metabolism and lactate production can foster the activated state of EGFR receptor and suggests that the inhibition of EGFR-mediated signaling can be attempted by means of CRM197 administered with an appropriate protease inhibitor. This attempt could help in overcoming the problem of the acquired resistance to the conventionally used EGFR inhibitors.
    Keywords:  EGFR; HBEGF; cancer cell metabolism; lactate
    DOI:  https://doi.org/10.3390/cells13181533
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