bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023‒05‒21
ten papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. IL-6 is dispensable for causing cachexia in the colon carcinoma 26 model.
  2. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer.
  3. Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice.
  4. Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.
  5. Contribution of adipocyte Na/K-ATPase α1/CD36 signaling induced exosome secretion in response to oxidized LDL.
  6. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
  7. Hypoxia-inducible factor-1α regulates the interleukin-6 production by B cells in rheumatoid arthritis.
  8. The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.
  9. Impact of acute stress on murine metabolomics and metabolic flux.
  10. LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
  1. bioRxiv. 2023 May 02. pii: 2023.05.02.539076. [Epub ahead of print]
    IL-6 is dispensable for causing cachexia in the colon carcinoma 26 model.
    Young-Yon Kwon, Sheng Hui.
      Various cytokines have been implicated in cancer cachexia. One such cytokine is IL-6, which has been deemed a key cachectic factor in mice inoculated with the colon carcinoma 26 (C26) cells, one of the most widely used models of cancer cachexia. Here to test the causal role of IL-6 in cancer cachexia, we used CRISPR/Cas9 editing to knock out IL-6 in C26 cells. We found that growth of IL-6 KO C26 tumors was dramatically delayed. Most strikingly, while IL-6 KO tumors eventually reached the similar size as wild-type tumors, cachexia still took place, despite no elevation in circulating IL-6. We further showed an increase of immune cell populations in IL-6 KO tumors and the defective IL-6 KO tumor growth was rescued in immunodeficient mice. Thus, our results invalidated IL-6 as a necessary factor for causing cachexia in the C26 model and revealed instead its important role in regulating tumor growth via immune suppression.
    DOI:  https://doi.org/10.1101/2023.05.02.539076
  2. Front Immunol. 2023 ;14 1163585
    The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer.
    Lincoln N Strickland, Erika Y Faraoni, Wei Ruan, Xiaoyi Yuan, Holger K Eltzschig, Jennifer M Bailey-Lundberg.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γδ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells.
    Keywords:  Adenosine receptor 2B; CD8+ T cell response; hypoxia; immunotherapy; pancreatic adenocarcinoma
    DOI:  https://doi.org/10.3389/fimmu.2023.1163585
  3. J Cachexia Sarcopenia Muscle. 2023 May 16.
    Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice.
    Steffen H Raun, Mona S Ali, Xiuqing Han, Carlos Henríquez-Olguín, T C Phung Pham, Roberto Meneses-Valdés, Jonas R Knudsen, Anna C H Willemsen, Steen Larsen, Thomas E Jensen, Ramon Langen, Lykke Sylow.
      BACKGROUND: Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia.METHODS: In vastus lateralis muscle biopsies from n = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38). Moreover, male LLC-tumour-bearing mice were treated with (n = 10)/without (n = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-d-glucose (2-DG) uptake and immunoblotting.
    RESULTS: Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat-free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: -35%, soleus: -49%, extensor digitorum longus: -48%) and the heart (-29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4thr642 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued cancer-induced insulin intolerance.
    CONCLUSIONS: Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK-deficient mice developing metabolic dysfunction in response to cancer, including AMPK-dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and possibly cachexia.
    Keywords:  AMP-activated protein kinase (AMPK); cancer cachexia; glucose metabolism; insulin resistance; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13238
  4. Cell Commun Signal. 2023 May 19. 21(1): 116
    Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation.
    Chuwen Jiang, Zhengting Jiang, Gengyu Sha, Daorong Wang, Dong Tang.
      Metastasis, the spread of a tumor or cancer from the primary site of the body to a secondary site, is a multi-step process in cancer progression, accounting for various obstacles in cancer treatment and most cancer-related deaths. Metabolic reprogramming refers to adaptive metabolic changes that occur in cancer cells in the tumor microenvironment (TME) to enhance their survival ability and metastatic potential. Stromal cell metabolism also changes to stimulate tumor proliferation and metastasis. Metabolic adaptations of tumor and non-tumor cells exist not only in the TME but also in the pre-metastatic niche (PMN), a remote TME conducive for tumor metastasis. As a novel mediator in cell-to-cell communication, small extracellular vesicles (sEVs), which have a diameter of 30-150 nm, reprogram metabolism in stromal and cancer cells within the TME by transferring bioactive substances including proteins, mRNAs and miRNAs (microRNAs). sEVs can be delivered from the primary TME to PMN, affecting PMN formation in stroma rewriting, angiogenesis, immunological suppression and matrix cell metabolism by mediating metabolic reprogramming. Herein, we review the functions of sEVs in cancer cells and the TME, how sEVs facilitate PMN establishment to trigger metastasis via metabolic reprogramming, and the prospective applications of sEVs in tumor diagnosis and treatment. Video Abstract.
    Keywords:  Metabolic reprogramming; Metastasis; PMN; Tumor microenvironment; sEVs
    DOI:  https://doi.org/10.1186/s12964-023-01136-x
  5. Front Cardiovasc Med. 2023 ;10 1046495
    Contribution of adipocyte Na/K-ATPase α1/CD36 signaling induced exosome secretion in response to oxidized LDL.
    Sneha S Pillai, Duane G Pereira, Jue Zhang, Wenxin Huang, Mirza Ahmar Beg, Darcy A Knaack, Bruno de Souza Goncalves, Daisy Sahoo, Roy L Silverstein, Joseph I Shapiro, Komal Sodhi, Yiliang Chen.
      Introduction: Adipose tissue constantly secretes adipokines and extracellular vesicles including exosomes to crosstalk with distinct tissues and organs for whole-body homeostasis. However, dysfunctional adipose tissue under chronic inflammatory conditions such as obesity, atherosclerosis, and diabetes shows pro-inflammatory phenotypes accompanied by oxidative stress and abnormal secretion. Nevertheless, molecular mechanisms of how adipocytes are stimulated to secrete exosomes under those conditions remain poorly understood.Methods: Mouse and human in vitro cell culture models were used for performing various cellular and molecular studies on adipocytes and macrophages. Statistical analysis was performed using Student's t-test (two-tailed, unpaired, and equal variance) for comparisons between two groups or ANOVA followed by Bonferroni's multiple comparison test for comparison among more than two groups.
    Results and discussion: In this work, we report that CD36, a scavenger receptor for oxidized LDL, formed a signaling complex with another membrane signal transducer Na/K-ATPase in adipocytes. The atherogenic oxidized LDL induced a pro-inflammatory response in in vitro differentiated mouse and human adipocytes and also stimulated the cells to secrete more exosomes. This was largely blocked by either CD36 knockdown using siRNA or pNaKtide, a peptide inhibitor of Na/K-ATPase signaling. These results showed a critical role of the CD36/Na/K-ATPase signaling complex in oxidized LDL-induced adipocyte exosome secretion. Moreover, by co-incubation of adipocyte-derived exosomes with macrophages, we demonstrated that oxidized LDL-induced adipocyte-derived exosomes promoted pro-atherogenic phenotypes in macrophages, including CD36 upregulation, IL-6 secretion, metabolic switch to glycolysis, and mitochondrial ROS production. Altogether, we show here a novel mechanism through which adipocytes increase exosome secretion in response to oxidized LDL and that the secreted exosomes can crosstalk with macrophages, which may contribute to atherogenesis.
    Keywords:  CD36; Na/K-ATPase; ROS; adipocyte; exosomes; macrophage; mitochondria; oxLDL
    DOI:  https://doi.org/10.3389/fcvm.2023.1046495
  6. Cell Metab. 2023 May 05. pii: S1550-4131(23)00171-7. [Epub ahead of print]
    Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
    Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang.
      Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
    Keywords:  CD8(+) T cell activation; FH; ZAP70; anti-tumor immune response; fumarate; fumarate hydrolase; succination; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.017
  7. Clin Transl Immunology. 2023 ;12(5): e1447
    Hypoxia-inducible factor-1α regulates the interleukin-6 production by B cells in rheumatoid arthritis.
    Chaofan Fan, Jia Li, Yixuan Li, Yuyang Jin, Jiaqi Feng, Ruru Guo, Xinyu Meng, Dongcheng Gong, Qian Chen, Fang Du, Chunyan Zhang, Liangjing Lu, Jun Deng, Xiao-Xiang Chen.
      Objectives: Rheumatoid arthritis (RA) is a disease characterised by bone destruction and systemic inflammation, and interleukin-6 (IL-6) is a therapeutic target for treating it. The study aimed at investigating the sources of IL-6 and the influence of hypoxia-inducible factor-1α (HIF-1α) on IL-6 production by B cells in RA patients.Methods: The phenotype of IL-6-producing cells in the peripheral blood of RA patients was analysed using flow cytometry. Bioinformatics, real-time polymerase chain reaction, Western blot and immunofluorescence staining were used to determine the IL-6 production and HIF-1α levels in B cells. A dual-luciferase reporter assay and chromatin immunoprecipitation were used to investigate the regulatory role of HIF-1α on IL-6 production in human and mouse B cells.
    Results: Our findings revealed that B cells are major sources of IL-6 in the peripheral blood of RA patients, with the proportion of IL-6-producing B cells significantly correlated with RA disease activity. The CD27-IgD+ naïve B cell subset was identified as the typical IL-6-producing subset in RA patients. Both HIF-1α and IL-6 were co-expressed by B cells in the peripheral blood and synovium of RA patients, and HIF-1α was found to directly bind to the IL6 promoter and enhance its transcription.
    Conclusion: This study highlights the role of B cells in producing IL-6 and the regulation of this production by HIF-1α in patients with RA. Targeting HIF-1α might provide a new therapeutic strategy for treating RA.
    Keywords:  B cells; HIF‐1α; IL‐6; rheumatoid arthritis
    DOI:  https://doi.org/10.1002/cti2.1447
  8. Front Immunol. 2023 ;14 1172931
    The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.
    Shonik Ganjoo, Priti Gupta, Halil Ibrahim Corbali, Selene Nanez, Thomas S Riad, Lisa K Duong, Hampartsoum B Barsoumian, Fatemeh Masrorpour, Hong Jiang, James W Welsh, Maria Angelica Cortez.
      Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.
    Keywords:  T cell; cancer; immunotherapy; metabolism; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1172931
  9. Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2301215120
    Impact of acute stress on murine metabolomics and metabolic flux.
    Won Dong Lee, Lingfan Liang, Jenna AbuSalim, Connor S R Jankowski, Laith Z Samarah, Michael D Neinast, Joshua D Rabinowitz.
      Plasma metabolite concentrations and labeling enrichments are common measures of organismal metabolism. In mice, blood is often collected by tail snip sampling. Here, we systematically examined the effect of such sampling, relative to gold-standard sampling from an in-dwelling arterial catheter, on plasma metabolomics and stable isotope tracing. We find marked differences between the arterial and tail circulating metabolome, which arise from two major factors: handling stress and sampling site, whose effects were deconvoluted by taking a second arterial sample immediately after tail snip. Pyruvate and lactate were the most stress-sensitive plasma metabolites, rising ~14 and ~5-fold. Both acute handling stress and adrenergic agonists induce extensive, immediate production of lactate, and modest production of many other circulating metabolites, and we provide a reference set of mouse circulatory turnover fluxes with noninvasive arterial sampling to avoid such artifacts. Even in the absence of stress, lactate remains the highest flux circulating metabolite on a molar basis, and most glucose flux into the TCA cycle in fasted mice flows through circulating lactate. Thus, lactate is both a central player in unstressed mammalian metabolism and strongly produced in response to acute stress.
    Keywords:  catecholamine; in vivo; isotope tracing; metabolomics; stress
    DOI:  https://doi.org/10.1073/pnas.2301215120
  10. Mol Cell. 2023 May 02. pii: S1097-2765(23)00288-5. [Epub ahead of print]
    LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
    Shelby E Compton, Susan M Kitchen-Goosen, Lisa M DeCamp, Kin H Lau, Batsirai Mabvakure, Matthew Vos, Kelsey S Williams, Kwok-Kin Wong, Xiaobing Shi, Scott B Rothbart, Connie M Krawczyk, Russell G Jones.
      Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.
    Keywords:  CREB; CREB-regulated transcription coactivator 2; CRTC2; H3K27; IL-1β; IL-6; LIF; LKB1; SIKs; cAMP response element binding protein; histone acetylation; inflammation; interleukin-6; leukemia inhibitory factor; liver kinase B1; salt-inducible kinases
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.017
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