bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023‒10‒15
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.
  2. Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.
  3. The intersection of HIF-1α, O-GlcNAc, and skeletal muscle loss in chronic obstructive pulmonary disease.
  4. The Immune Regulatory Role of Adenosine in the Tumor Microenvironment.
  5. TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content.
  6. Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
  7. The cancer-immune dialogue in the context of stress.
  1. Front Endocrinol (Lausanne). 2023 ;14 1264530
    The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.
    Jayashree Jena, Luis Miguel García-Peña, Renata O Pereira.
      Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.
    Keywords:  FGF21; GDF15; energy balance; integrated stress response; metabolic health; mitochondrial stress
    DOI:  https://doi.org/10.3389/fendo.2023.1264530
  2. Clin Cancer Res. 2023 Oct 11.
    Nuclear GRP78 Promotes Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma.
    Tiansuo Zhao, Tingting Jiang, Xiaojia Li, Shaofei Chang, Qihui Sun, Fanyang Kong, Xiangyu Kong, Fang Wei, Jie He, Jihui Hao, Keping Xie.
      PURPOSE: Stromal fibrosis limits nutritional supply and disarrays metabolism in pancreatic cancer (PDA). Understanding of the molecular basis underlying metabolic cues would improve PDA management. The current study determined the interaction between glucose-regulated proteins 78 (GRP78) and hypoxia-inducible factor 1a (HIF-1a) and its mechanistic roles underlying PDA response to oxygen and glucose restrains.EXPERIMENTAL DESIGN: Gene expression in and its association with clinicopathologic characteristics of PDA patients and mouse models were analyzed using immunohistochemistry. Protein expression and their regulation were measured by Western blot and immunoprecipitation analyses. Protein interactions were determined using gain- and loss-of-function assays and molecular methods, including chromatin immunoprecipitation, co-Immunoprecipitation and dual luciferase reporter.
    RESULTS: There were concomitant overexpression of both GRP78 and HIF-1a in human and mouse PDA tissues and cells. Glucose deprivation increased the expression of GRP78 and HIF-1a, particularly colocalization in nucleus. Induction of HIF-1a expression by glucose deprivation in PDA cells depended on the expression of and its own interaction with GRP78. Mechanistically, increased expression of both HIF-1a and LDHA under glucose deprivation was caused by the direct binding of GRP78 and HIF-1a protein complexes to the promoters of HIF-1a and LDHA genes and transactivation of their transcriptional activity.
    CONCLUSIONS: Protein complex of GRP78 and HIF-1a directly binds to HIF-1a own promoter and LDHA promoter, enhances the transcription of both HIF-1a and LDHA, while glucose deprivation increases GRP78 expression and further enhances HIF-1a and LDHA transcription. Therefore, crosstalk and integration of hypoxia- and hypoglycemia-responsive signaling critically impact PDA metabolic reprogramming and therapeutic resistance.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1143
  3. Glycobiology. 2023 Oct 09. pii: cwad081. [Epub ahead of print]
    The intersection of HIF-1α, O-GlcNAc, and skeletal muscle loss in chronic obstructive pulmonary disease.
    Jinendiran Sekar, Amy Attaway.
      Sarcopenia, defined as the loss of muscle mass and strength, is a major cause of morbidity and mortality in COPD (chronic obstructive pulmonary disease) patients. However, the molecular mechanisms that cause sarcopenia remain to be determined. In this review, we will highlight the unique molecular and metabolic perturbations that occur in the skeletal muscle of COPD patients in response to hypoxia, and emphasize important areas of future research. In particular, the mechanisms related to the glycolytic shift that occurs in skeletal muscle in response to hypoxia may occur via a hypoxia-inducible factor 1-alpha (HIF-1α)-mediated mechanism. Upregulated glycolysis in skeletal muscle promotes a unique post-translational glycosylation of proteins known as O-GlcNAcylation, which further shifts metabolism towards glycolysis. Molecular changes in the skeletal muscle of COPD patients are associated with fiber-type shifting from Type I (oxidative) muscle fibers to Type II (glycolytic) muscle fibers. The metabolic shift towards glycolysis caused by HIF-1α and O-GlcNAc modified proteins suggests a potential cause for sarcopenia in COPD, which is an emerging area of future research.
    Keywords:  COPD; HIF-1α; O-GlcNAcylation; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1093/glycob/cwad081
  4. Int J Mol Sci. 2023 Oct 05. pii: 14928. [Epub ahead of print]24(19):
    The Immune Regulatory Role of Adenosine in the Tumor Microenvironment.
    Jianlei Xing, Jinhua Zhang, Jinyan Wang.
      Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities by inducing tumor cell proliferation, migration or invasion, tumor tissue angiogenesis, and chemoresistance. In addition, adenosine plays an important role in regulating anti-tumor immune responses and facilitating tumor immune escape. Adenosine receptors are broadly expressed by tumor-infiltrated immune cells, including suppressive tumor-associated macrophages and CD4+ regulatory T cells, as well as effector CD4+ T cells and CD8+ cytotoxic T lymphocytes. Therefore, adenosine is indispensable in down-regulating anti-tumor immune responses in the tumor microenvironment and contributes to tumor progression. This review describes the current progress on the role of adenosine/adenosine receptor pathway in regulating the tumor-infiltrating immune cells that contribute to tumor immune evasion and aims to provide insights into adenosine-targeted tumor immunotherapy.
    Keywords:  CD39; CD73; adenosine; tumor immunotherapy
    DOI:  https://doi.org/10.3390/ijms241914928
  5. Front Immunol. 2023 ;14 1209249
    TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype and is associated with increased survival in cancer patients with high tumor macrophage content.
    Sinem Gunalp, Derya Goksu Helvaci, Aysenur Oner, Ahmet Bursalı, Alessandra Conforte, Hüseyin Güner, Gökhan Karakülah, Eva Szegezdi, Duygu Sag.
      Background: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can either induce cell death or activate survival pathways after binding to death receptors (DRs) DR4 or DR5. TRAIL is investigated as a therapeutic agent in clinical trials due to its selective toxicity to transformed cells. Macrophages can be polarized into pro-inflammatory/tumor-fighting M1 macrophages or anti-inflammatory/tumor-supportive M2 macrophages and an imbalance between M1 and M2 macrophages can promote diseases. Therefore, identifying modulators that regulate macrophage polarization is important to design effective macrophage-targeted immunotherapies. The impact of TRAIL on macrophage polarization is not known.Methods: Primary human monocyte-derived macrophages were pre-treated with either TRAIL or with DR4 or DR5-specific ligands and then polarized into M1, M2a, or M2c phenotypes in vitro. The expression of M1 and M2 markers in macrophage subtypes was analyzed by RNA sequencing, qPCR, ELISA, and flow cytometry. Furthermore, the cytotoxicity of the macrophages against U937 AML tumor targets was assessed by flow cytometry. TCGA datasets were also analyzed to correlate TRAIL with M1/M2 markers, and the overall survival of cancer patients.
    Results: TRAIL increased the expression of M1 markers at both mRNA and protein levels while decreasing the expression of M2 markers at the mRNA level in human macrophages. TRAIL also shifted M2 macrophages towards an M1 phenotype. Our data showed that both DR4 and DR5 death receptors play a role in macrophage polarization. Furthermore, TRAIL enhanced the cytotoxicity of macrophages against the AML cancer cells in vitro. Finally, TRAIL expression was positively correlated with increased expression of M1 markers in the tumors from ovarian and sarcoma cancer patients and longer overall survival in cases with high, but not low, tumor macrophage content.
    Conclusions: TRAIL promotes the polarization of human macrophages toward a proinflammatory M1 phenotype via both DR4 and DR5. Our study defines TRAIL as a new regulator of macrophage polarization and suggests that targeting DRs can enhance the anti-tumorigenic response of macrophages in the tumor microenvironment by increasing M1 polarization.
    Keywords:  TRAIL; death receptors; macrophage cytotoxicity; macrophage polarization; primary human macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1209249
  6. Mol Cell Biol. 2023 ;43(10): 531-546
    Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.
    Leah I Susser, My-Anh Nguyen, Michele Geoffrion, Christina Emerton, Mireille Ouimet, Mireille Khacho, Katey J Rayner.
      During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.
    Keywords:  fission; fusion; histone lactylation; inflammation resolution; macrophages; mitochondrial metabolism
    DOI:  https://doi.org/10.1080/10985549.2023.2253131
  7. Nat Rev Immunol. 2023 Oct 13.
    The cancer-immune dialogue in the context of stress.
    Yuting Ma, Guido Kroemer.
      Although there is little direct evidence supporting that stress affects cancer incidence, it does influence the evolution, dissemination and therapeutic outcomes of neoplasia, as shown in human epidemiological analyses and mouse models. The experience of and response to physiological and psychological stressors can trigger neurological and endocrine alterations, which subsequently influence malignant (stem) cells, stromal cells and immune cells in the tumour microenvironment, as well as systemic factors in the tumour macroenvironment. Importantly, stress-induced neuroendocrine changes that can regulate immune responses have been gradually uncovered. Numerous stress-associated immunomodulatory molecules (SAIMs) can reshape natural or therapy-induced antitumour responses by engaging their corresponding receptors on immune cells. Moreover, stress can cause systemic or local metabolic reprogramming and change the composition of the gastrointestinal microbiota which can indirectly modulate antitumour immunity. Here, we explore the complex circuitries that link stress to perturbations in the cancer-immune dialogue and their implications for therapeutic approaches to cancer.
    DOI:  https://doi.org/10.1038/s41577-023-00949-8
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒22 at 14:53.