bims-stacyt 2023-02-26 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023‒02‒26
ten papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment.
Berberine ameliorates obesity by inducing GDF15 secretion by brown adipocytes.
Metabolic programming and immune suppression in the tumor microenvironment.
Crosstalk between fatty acid metabolism and tumour-associated macrophages in cancer progression.
Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop.
An adverse tumor-protective effect of IDO1 inhibition.
Neurotoxicity of ischemic astrocytes involves STAT3-mediated metabolic switching and depends on glycogen usage.
PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy.
Intermittent hypoxia treatments cause cellular priming in human microglia.
Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming.

EMBO J. 2023 Feb 20. e112067

HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment.

Rindert Missiaen, Nicholas P Lesner, M Celeste Simon.

  A role for hypoxia-inducible factors (HIFs) in hypoxia-dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF-dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF-dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia-dependent alterations by activating HIF-dependent transcription to alter nutrient import, export, and utilization. In recent years, the concept of metabolic competition has been proposed for critical substrates, including glucose, lactate, glutamine, arginine, and tryptophan. In this review, we discuss how HIF-mediated mechanisms control nutrient sensing and availability in the TME, the competition for nutrients, and the metabolic cross-talk between tumor and stromal cells.

Keywords:  HIF; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.15252/embj.2022112067
Endocrinology. 2023 Feb 24. pii: bqad035. [Epub ahead of print]

Berberine ameliorates obesity by inducing GDF15 secretion by brown adipocytes.

Chang Li, Qingyang Leng, Lihua Li, Fan Hu, Yuejie Xu, Sa Gong, Ying Yang, Hongli Zhang, Xiaohua Li.

  Berberine (BBR), which is a compound derived from the Chinese medicinal plant Coptis chinensis, promotes weight loss, but the molecular mechanisms are not well understood. Here, we show that BBR increases the serum level of growth differentiation factor 15 (GDF15), which is a stress response cytokine that can reduce food intake and lower body weight in diet-induced obese (DIO) mice. The body weight and food intake of DIO mice were decreased after BBR treatment, and the weight change was negatively correlated with the serum GDF15 level. Further studies show that BBR induced GDF15 mRNA expression and secretion in the brown adipose tissue (BAT) of DIO mice and primary mouse brown adipocytes. In addition, we found that BBR upregulates GDF15 mRNA expression and secretion by activating the integrated stress response (ISR) in primary mouse brown adipocytes. Overall, our findings show that BBR lowers body weight by inducing GDF15 secretion via the activation of the ISR in BAT.

Keywords:  Berberine; Brown adipocytes; GDF15; Integrated Stress Response; Obesity

DOI:  https://doi.org/10.1210/endocr/bqad035
Cancer Cell. 2023 Feb 09. pii: S1535-6108(23)00009-0. [Epub ahead of print]

Metabolic programming and immune suppression in the tumor microenvironment.

Emily N Arner, Jeffrey C Rathmell.

  Increased glucose metabolism and uptake are characteristic of many tumors and used clinically to diagnose and monitor cancer progression. In addition to cancer cells, the tumor microenvironment (TME) encompasses a wide range of stromal, innate, and adaptive immune cells. Cooperation and competition between these cell populations supports tumor proliferation, progression, metastasis, and immune evasion. Cellular heterogeneity leads to metabolic heterogeneity because metabolic programs within the tumor are dependent not only on the TME cellular composition but also on cell states, location, and nutrient availability. In addition to driving metabolic plasticity of cancer cells, altered nutrients and signals in the TME can lead to metabolic immune suppression of effector cells and promote regulatory immune cells. Here we discuss how metabolic programming of cells within the TME promotes tumor proliferation, progression, and metastasis. We also discuss how targeting metabolic heterogeneity may offer therapeutic opportunities to overcome immune suppression and augment immunotherapies.

Keywords:  immune; metabolism; metastasis; plasticity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2023.01.009
Biomedicine (Taipei). 2022 ;12(4): 9-19

Crosstalk between fatty acid metabolism and tumour-associated macrophages in cancer progression.

Noorzaileen Eileena Zaidi, Nur Aima Hafiza Shazali, Thean Chor Leow, Mohd Azuraidi Osman, Kamariah Ibrahim, Nik Mohd Afizan Nik Abd Rahman.

  Over the last few decades, cancer has been regarded as an independent and self sustaining progression. The earliest hallmarks of cancer comprise of sustaining proliferative signalling, avoiding growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Nonetheless, two emerging hallmarks are being described: aberrant metabolic pathways and evasion of immune destruction. Changes in tumour cell metabolism are not restricted to tumour cells alone; the products of the altered metabolism have a direct impact on the activity of immune cells inside the tumour microenvironment, particularly tumour-associated macrophages (TAMs). The complicated process of cancer growth is orchestrated by metabolic changes dictating the tight mutual connection between these cells. Here, we discuss approaches to exploit the interaction of cancer cells' abnormal metabolic activity and TAMs. We also describe ways to exploit it by reprogramming fatty acid metabolism via TAMs.

Keywords:  Fatty acid metabolism; Invasion; Metastasis; Oleic acid; Palmitic acid; Tumour-associated macrophages

DOI:  https://doi.org/10.37796/2211-8039.1381
Anal Cell Pathol (Amst). 2023 ;2023 8334881

Interleukin-6 and Hypoxia Synergistically Promote EMT-Mediated Invasion in Epithelial Ovarian Cancer via the IL-6/STAT3/HIF-1α Feedback Loop.

Tongshuo Zhang, Jing Yang, Yang Sun, Jiangnan Song, Dandan Gao, Suhui Huang, Aibo Pang, Jianhui Zhang, Junhong Wang, Yue Wang, Yanqiu Li.

Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial-mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.

DOI: https://doi.org/10.1155/2023/8334881
Cell Rep Med. 2023 Feb 21. pii: S2666-3791(23)00033-2. [Epub ahead of print]4(2): 100941

An adverse tumor-protective effect of IDO1 inhibition.

Juliana C N Kenski, Xinyao Huang, David W Vredevoogd, Beaunelle de Bruijn, Joleen J H Traets, Sofía Ibáñez-Molero, Sebastiaan M Schieven, Alex van Vliet, Oscar Krijgsman, Thomas Kuilman, Joanna Pozniak, Fabricio Loayza-Puch, Alexandra M Terry, Judith Müller, Meike E W Logtenberg, Marjolein de Bruijn, Pierre Levy, Pierre-René Körner, Colin R Goding, Ton N Schumacher, Jean-Christophe Marine, Reuven Agami, Daniel S Peeper.

  By restoring tryptophan, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors aim to reactivate anti-tumor T cells. However, a phase III trial assessing their clinical benefit failed, prompting us to revisit the role of IDO1 in tumor cells under T cell attack. We show here that IDO1 inhibition leads to an adverse protection of melanoma cells to T cell-derived interferon-gamma (IFNγ). RNA sequencing and ribosome profiling shows that IFNγ shuts down general protein translation, which is reversed by IDO1 inhibition. Impaired translation is accompanied by an amino acid deprivation-dependent stress response driving activating transcription factor-4 (ATF4)high/microphtalmia-associated transcription factor (MITF)low transcriptomic signatures, also in patient melanomas. Single-cell sequencing analysis reveals that MITF downregulation upon immune checkpoint blockade treatment predicts improved patient outcome. Conversely, MITF restoration in cultured melanoma cells causes T cell resistance. These results highlight the critical role of tryptophan and MITF in the melanoma response to T cell-derived IFNγ and uncover an unexpected negative consequence of IDO1 inhibition.

Keywords:  IDO1; IDO1 inhibition; IFNgamma; MITF; T cells; clinical trial; immunotherapy; melanoma; translation

DOI:  https://doi.org/10.1016/j.xcrm.2023.100941
Glia. 2023 Feb 22.

Neurotoxicity of ischemic astrocytes involves STAT3-mediated metabolic switching and depends on glycogen usage.

Mina Borbor, Dongpei Yin, Ulf Brockmeier, Chen Wang, Marius Doeckel, Matthias Pillath-Eilers, Britta Kaltwasser, Dirk M Hermann, Egor Dzyubenko.

  Astrocytic responses are critical for the maintenance of neuronal networks in health and disease. In stroke, reactive astrocytes undergo functional changes potentially contributing to secondary neurodegeneration, but the mechanisms of astrocyte-mediated neurotoxicity remain elusive. Here, we investigated metabolic reprogramming in astrocytes following ischemia-reperfusion in vitro, explored their role in synaptic degeneration, and verified the key findings in a mouse model of stroke. Using indirect cocultures of primary mouse astrocytes and neurons, we demonstrate that transcription factor STAT3 controls metabolic switching in ischemic astrocytes promoting lactate-directed glycolysis and hindering mitochondrial function. Upregulation of astrocytic STAT3 signaling associated with nuclear translocation of pyruvate kinase isoform M2 and hypoxia response element activation. Reprogrammed thereby, the ischemic astrocytes induced mitochondrial respiration failure in neurons and triggered glutamatergic synapse loss, which was prevented by inhibiting astrocytic STAT3 signaling with Stattic. The rescuing effect of Stattic relied on the ability of astrocytes to utilize glycogen bodies as an alternative metabolic source supporting mitochondrial function. After focal cerebral ischemia in mice, astrocytic STAT3 activation was associated with secondary synaptic degeneration in the perilesional cortex. Inflammatory preconditioning with LPS increased astrocytic glycogen content, reduced synaptic degeneration, and promoted neuroprotection post stroke. Our data indicate the central role of STAT3 signaling and glycogen usage in reactive astrogliosis and suggest novel targets for restorative stroke therapy.

Keywords:  astrocyte-neuronal interaction; cerebral ischemia; glycolysis; metabolic reprogramming; neuroprotection; oxidative phosphorylation; synaptic degeneration

DOI:  https://doi.org/10.1002/glia.24357
Cell Metab. 2023 Feb 16. pii: S1550-4131(23)00010-4. [Epub ahead of print]

PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy.

Duo Zhang, Albert M Li, Guanghui Hu, Menggui Huang, Fan Yang, Lin Zhang, Kathryn E Wellen, Xiaowei Xu, Crystal S Conn, Wei Zou, Mark Kahn, Seth D Rhoades, Aalim M Weljie, Serge Y Fuchs, Nduka Amankulor, Daniel Yoshor, Jiangbin Ye, Constantinos Koumenis, Yanqing Gong, Yi Fan.

  The efficacy of immunotherapy is limited by the paucity of T cells delivered and infiltrated into the tumors through aberrant tumor vasculature. Here, we report that phosphoglycerate dehydrogenase (PHGDH)-mediated endothelial cell (EC) metabolism fuels the formation of a hypoxic and immune-hostile vascular microenvironment, driving glioblastoma (GBM) resistance to chimeric antigen receptor (CAR)-T cell immunotherapy. Our metabolome and transcriptome analyses of human and mouse GBM tumors identify that PHGDH expression and serine metabolism are preferentially altered in tumor ECs. Tumor microenvironmental cues induce ATF4-mediated PHGDH expression in ECs, triggering a redox-dependent mechanism that regulates endothelial glycolysis and leads to EC overgrowth. Genetic PHGDH ablation in ECs prunes over-sprouting vasculature, abrogates intratumoral hypoxia, and improves T cell infiltration into the tumors. PHGDH inhibition activates anti-tumor T cell immunity and sensitizes GBM to CAR T therapy. Thus, reprogramming endothelial metabolism by targeting PHGDH may offer a unique opportunity to improve T cell-based immunotherapy.

Keywords:  ATF4; CAR T immunotherapy; PHGDH; endothelial metabolism; glycolysis; vascular pruning

DOI:  https://doi.org/10.1016/j.cmet.2023.01.010
J Cell Mol Med. 2023 Feb 23.

Intermittent hypoxia treatments cause cellular priming in human microglia.

Martina De Felice, Lorenzo Germelli, Rebecca Piccarducci, Eleonora Da Pozzo, Chiara Giacomelli, Anna Baccaglini-Frank, Claudia Martini.

  Obstructive sleep apnoea syndrome (OSAS) is a sleep-disordered breathing characterized by nocturnal collapses of the upper airway resulting in cycles of blood oxygen partial pressure oscillations, which lead to tissue and cell damage due to intermittent hypoxia (IH) episodes. Since OSAS-derived IH may lead to cognitive impairment through not fully cleared mechanisms, herein we developed a new in vitro model mimicking IH conditions to shed light on its molecular effects on microglial cells, with particular attention to the inflammatory response. The in vitro model was set-up and validated by measuring the hypoxic state, HIF-1α levels, oxidative stress by ROS production and mitochondrial activity by MTS assay. Then, the mRNA and protein levels of certain inflammatory markers (NF-κB and interleukin 6 (IL-6)) after different IH treatment protocols were investigated. The IH treatments followed by a normoxic period were not able to produce a high inflammatory state in human microglial cells. Nevertheless, microglia appeared to be in a state characterized by increased expression of NF-κB and markers related to a primed phenotype. The microglia exposed to IH cycles and stimulated with exogenous IL-1β resulted in an exaggerated inflammatory response with increased NF-κB and IL-6 expression, suggesting a role for primed microglia in OSAS-driven neuroinflammation.

Keywords:  CD86; HIF-1α; HLA-DRα; IL-6; NF-κB; intermittent hypoxia; microglial priming; mild cognitive impairment; neuroinflammation; obstructive sleep apnoea syndrome

DOI:  https://doi.org/10.1111/jcmm.17682
Sci Rep. 2023 Feb 24. 13(1): 3257

Bovine tumor necrosis factor-alpha Increases IL-6, IL-8, and PGE2 in bovine fibroblast-like synoviocytes by metabolic reprogramming.

Carolina Manosalva, Pablo Alarcon, John Quiroga, Stefanie Teuber, Maria D Carretta, Hedie Bustamante, Rodrigo Lopez-Muñoz, Maria A Hidalgo, Rafael A Burgos.

Lameness is a common condition in dairy cattle caused by infectious or noninfectious agents. Joint lesions are the second most common cause of lameness and can be diagnosed in association with the presentation of digit injuries. Fibroblast-like synoviocyte (FLS) are predominant cells of synovia and play a key role in the pathophysiology of joint diseases, thus increasing the expression of proinflammatory mediators. Tumor necrosis factor-alpha (TNF-α) is a potent proinflammatory cytokine involved in cyclooxygenase 2 (COX-2) and proinflammatory cytokine expression in FLS. Previously, TNF-α was demonstrated to increase hypoxia-inducible Factor 1 (HIF-1), a transcription factor that rewires cellular metabolism and increases the expression of interleukin (IL)-6 in bovine FLS (bFLS). Despite this, the proinflammatory effects of TNF-α in bFLS on metabolic reprogramming have been poorly studied. We hypothesized that TNF-α increases glycolysis and in this way controls the expression of IL-6, IL-8, and COX-2 in bFLS. Results first, gas chromatography/mass spectrometry (GC/MS)-based untargeted metabolomics revealed that bTNF-α altered the metabolism of bFLS, increasing glucose, isoleucine, leucine, methionine, valine, tyrosine, and lysine and decreasing malate, fumarate, α-ketoglutarate, stearate, palmitate, laurate, aspartate, and alanine. In addition, metabolic flux analysis using D-glucose-13C6 demonstrated an increase of pyruvate and a reduction in malate and citrate levels, suggesting a decreased flux toward the tricarboxylic acid cycle after bTNF-α stimulation. However, bTNF-α increased lactate dehydrogenase subunit A (LDHA), IL-6, IL-8, IL-1β and COX-2 expression, which was dependent on glycolysis and the PI3K/Akt pathway. The use of FX11 and dichloroacetate (DCA), an inhibitor of LDHA and pyruvate dehydrogenase kinase (PDK) respectively, partially reduced the expression of IL-6. Our results suggest that bTNF-α induces metabolic reprogramming that favors glycolysis in bFLS and increases IL-6, IL-8, IL-1β and COX-2/PGE2.

DOI: https://doi.org/10.1038/s41598-023-29851-y