bims-stacyt 2024-06-23 papers

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–06–23
seventeen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.
Novel insights into the GCN2 pathway and its targeting. Therapeutic value in cancer and lessons from lung fibrosis development.
Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function.
Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.
Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.
Computational Modeling of the Synergistic Role of GCN2 and HPA Axis in Regulating the Integrated Stress Response in the Central Circadian Timing System.
A Senescence-Mimicking (Senomimetic) VEGFR TKI Side Effect Primes Tumor Immune Responses via IFN/STING Signaling.
Early short-term hypoxia promotes epidermal cell migration by activating the CCL2-ERK1/2 pathway and epithelial-mesenchymal transition during wound healing.
Lactate drives the ESM1-SCD1 axis to inhibit the antitumor CD8+ T-cell response by activating the Wnt/β-catenin pathway in ovarian cancer cells and inducing cisplatin resistance.
Extracellular vesicles originating from steatotic hepatocytes promote hepatic stellate cell senescence via AKT/mTOR signaling.
AMPK Regulates M1 Macrophage Polarization through the JAK2/STAT3 Signaling Pathway to Attenuate Airway Inflammation in Obesity-Related Asthma.
Lactate induces tumor progression via LAR motif-dependent Yin-Yang 1 degradation.
Inhibition of the eukaryotic initiation factor-2-α kinase PERK decreases risk of autoimmune diabetes in mice.
Interleukin-6 serves as a critical factor in various cancer progression and therapy.
Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy.
Growth differentiation factor 15 (GDF15) levels are associated with malnutrition in acutely admitted older adults.
Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Nat Commun. 2024 Jun 18. 15(1): 5190

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.

Pavlina Chrysafi, Laura Valenzuela-Vallejo, Konstantinos Stefanakis, Theodoros Kelesidis, Margery A Connelly, Christos S Mantzoros.

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

DOI: https://doi.org/10.1038/s41467-024-49366-y
FEBS J. 2024 Jun 16.

Novel insights into the GCN2 pathway and its targeting. Therapeutic value in cancer and lessons from lung fibrosis development.

Marie Piecyk, Carole Ferraro-Peyret, David Laville, Frédéric Perros, Cedric Chaveroux.

  Defining the mechanisms that allow cells to adapt to environmental stress is critical for understanding the progression of chronic diseases and identifying relevant drug targets. Among these, activation of the pathway controlled by the eIF2-alpha kinase GCN2 is critical for translational and metabolic reprogramming of the cell in response to various metabolic, proteotoxic, and ribosomal stressors. However, its role has frequently been investigated through the lens of a stress pathway signaling via the eIF2α-activating transcription factor 4 (ATF4) downstream axis, while recent advances in the field have revealed that the GCN2 pathway is more complex than previously thought. Indeed, this kinase can be activated through a variety of mechanisms, phosphorylate substrates other than eIF2α, and regulate cell proliferation in a steady state. This review presents recent findings regarding the fundamental mechanisms underlying GCN2 signaling and function, as well as the development of drugs that modulate its activity. Furthermore, by comparing the literature on GCN2's antagonistic roles in two challenging pathologies, cancer and pulmonary diseases, the benefits, and drawbacks of GCN2 targeting, particularly inhibition, are discussed.

Keywords:  GCN2; cancer; lung diseases; pharmacological modulation

DOI:  https://doi.org/10.1111/febs.17203
Front Immunol. 2024 ;15 1409238

Tumor glucose metabolism and the T cell glycocalyx: implication for T cell function.

Fabian Schuurmans, Kyra E Wagemans, Gosse J Adema, Lenneke A M Cornelissen.

  The T cell is an immune cell subset highly effective in eliminating cancer cells. Cancer immunotherapy empowers T cells and occupies a solid position in cancer treatment. The response rate, however, remains relatively low (<30%). The efficacy of immunotherapy is highly dependent on T cell infiltration into the tumor microenvironment (TME) and the ability of these infiltrated T cells to sustain their function within the TME. A better understanding of the inhibitory impact of the TME on T cells is crucial to improve cancer immunotherapy. Tumor cells are well described for their switch into aerobic glycolysis (Warburg effect), resulting in high glucose consumption and a metabolically distinct TME. Conversely, glycosylation, a predominant posttranslational modification of proteins, also relies on glucose molecules. Proper glycosylation of T cell receptors influences the immunological synapse between T cells and tumor cells, thereby affecting T cell effector functions including their cytolytic and cytostatic activities. This review delves into the complex interplay between tumor glucose metabolism and the glycocalyx of T cells, shedding light on how the TME can induce alterations in the T cell glycocalyx, which can subsequently influence the T cell's ability to target and eliminate tumor cells.

Keywords:  T cell glycocalyx; glycobiology; metabolism; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1409238
Cell Death Discov. 2024 Jun 19. 10(1): 292

Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.

Adrien Krug, Rana Mhaidly, Marie Tosolini, Laura Mondragon, Gamze Tari, Adriana Martinez Turtos, Rachel Paul-Bellon, Vahid Asnafi, Sandrine Marchetti, Léa Di Mascio, Marion Travert, Frédéric Bost, Emmanuel Bachy, Rafael J Argüello, Jean-Jacques Fournié, Philippe Gaulard, François Lemonnier, Jean-Ehrland Ricci, Els Verhoeyen.

Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.

DOI: https://doi.org/10.1038/s41420-024-02061-9
EMBO Rep. 2024 Jun 21.

Lactate supports cell-autonomous ECM production to sustain metastatic behavior in prostate cancer.

Luigi Ippolito, Assia Duatti, Marta Iozzo, Giuseppina Comito, Elisa Pardella, Nicla Lorito, Marina Bacci, Erica Pranzini, Alice Santi, Giada Sandrini, Carlo V Catapano, Sergio Serni, Pietro Spatafora, Andrea Morandi, Elisa Giannoni, Paola Chiarugi.

  Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.

Keywords:  CAFs; Collagen Hydroxylation; Collagen Signaling; Lactate Metabolism

DOI:  https://doi.org/10.1038/s44319-024-00180-z
Physiol Genomics. 2024 Jun 17.

Computational Modeling of the Synergistic Role of GCN2 and HPA Axis in Regulating the Integrated Stress Response in the Central Circadian Timing System.

Yannuo Li, Lingjun Lu, Jordan L Levy, Tracy G Anthony, Ioannis P Androulakis.

  The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semi-mechanistic mathematical model to delineate the suprachiasmatic nucleus (SCN)'s capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation reveals a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag, as well as to an elongation of the circadian period. These.

Keywords:  Circadian rhythms; GCN2; HPA; ISR; chronobiology

DOI:  https://doi.org/10.1152/physiolgenomics.00030.2024
Mol Cancer Ther. 2024 Jun 19. OF1-OF20

A Senescence-Mimicking (Senomimetic) VEGFR TKI Side Effect Primes Tumor Immune Responses via IFN/STING Signaling.

Melissa Dolan, Yuhao Shi, Michalis Mastri, Mark D Long, Amber McKenery, James W Hill, Cristina Vaghi, Sebastien Benzekry, Joseph Barbi, John M L Ebos.

Tyrosine kinase inhibitors (TKIs) that block the vascular endothelial growth factor receptors (VEGFRs) not only disrupt tumor angiogenesis but also have many unexpected side effects that impact tumor cells directly. This includes the induction of molecular markers associated with senescence, a form of cellular aging that typically involves growth arrest. We have shown that VEGFR TKIs can hijack these aging programs by transiently inducting senescence markers (SMs) in tumor cells to activate senescence-associated secretory programs that fuel drug resistance. Here we show that these same senescence-mimicking ("senomimetic") VEGFR TKI effects drive an enhanced immunogenic signaling that, in turn, can alter tumor response to immunotherapy. By using a live cell sorting method to detect β-galactosidase, a commonly used SM, we found that subpopulations of SM-expressing (SM+) tumor cells have heightened IFN signaling and increased expression of IFN-stimulated genes (ISGs). These ISGs increase under the control of the STimulator of the INterferon Gene (STING) signaling pathway, which we found could be directly activated by several VEGFR TKIs. TKI-induced SM+ cells could stimulate or suppress CD8 T-cell activation depending on host-tumor cell contact while tumors grown from SM+ cells were more sensitive to PDL1 inhibition in vivo, suggesting that offsetting immune-suppressive functions of SM+ cells can improve TKI efficacy overall. Our findings may explain why some (but not all) VEGFR TKIs improve outcomes when combined with immunotherapy and suggest that exploiting senomimetic drug side effects may help identify TKIs that uniquely "prime" tumors for enhanced sensitivity to PDL1-targeted agents.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0139
Burns Trauma. 2024 ;12 tkae017

Early short-term hypoxia promotes epidermal cell migration by activating the CCL2-ERK1/2 pathway and epithelial-mesenchymal transition during wound healing.

Linbo Jin, Shiqi Zhou, Shihan Zhao, Junhui Long, Zhidan Huang, Junli Zhou, Yiming Zhang.

   Background: Due to vasculature injury and increased oxygen consumption, the early wound microenvironment is typically in a hypoxic state. We observed enhanced cell migration ability under early short-term hypoxia. CCL2 belongs to the CC chemokine family and was found to be increased in early hypoxic wounds and enriched in the extracellular signal-regulated kinase (ERK)1/2 pathway in our previous study. However, the underlying mechanism through which the CCL2-ERK1/2 pathway regulates wound healing under early short-term hypoxia remains unclear. Activation of epithelial-mesenchymal transition (EMT) is a key process in cancer cell metastasis, during which epithelial cells acquire the characteristics of mesenchymal cells and enhance cell motility and migration ability. However, the relationship between epithelial cell migration and EMT under early short-term hypoxia has yet to be explored.
Methods: HaCaT cells were cultured to verify the effect of early short-term hypoxia on migration through cell scratch assays. Lentiviruses with silenced or overexpressed CCL2 were used to explore the relationship between CCL2 and migration under short-term hypoxia. An acute full-thickness cutaneous wound rat model was established with the application of an ERK inhibitor to reveal the hidden role of the ERK1/2 pathway in the early stage of wound healing. The EMT process was verified in all the above experiments through western blotting.
Results: In our study, we found that short-term hypoxia promoted cell migration. Mechanistically, hypoxia promoted cell migration through mediating CCL2. Overexpression of CCL2 via lentivirus promoted cell migration, while silencing CCL2 via lentivirus inhibited cell migration and the production of related downstream proteins. In addition, we found that CCL2 was enriched in the ERK1/2 pathway, and the application of an ERK inhibitor in vivo and in vitro verified the upstream and downstream relationships between the CCL2 pathway and ERK1/2. Western blot results both in vivo and in vitro demonstrated that early short-term hypoxia promotes epidermal cell migration by activating the CCL2-ERK1/2 pathway and EMT during wound healing.
Conclusions: Our work demonstrated that hypoxia in the early stage serves as a stimulus for triggering wound healing through activating the CCL2-ERK1/2 pathway and EMT, which promote epidermal cell migration and accelerate wound closure. These findings provide additional detailed insights into the mechanism of wound healing and new targets for clinical treatment.

Keywords:  CCL2; Epidermal cells; Epithelial–mesenchymal transition; Extracellular signal-regulated kinase; Hypoxia; Wound healing

DOI:  https://doi.org/10.1093/burnst/tkae017
Int Immunopharmacol. 2024 Jun 18. pii: S1567-5769(24)00982-2. [Epub ahead of print]137 112461

Lactate drives the ESM1-SCD1 axis to inhibit the antitumor CD8+ T-cell response by activating the Wnt/β-catenin pathway in ovarian cancer cells and inducing cisplatin resistance.

Zhiwen Fan, Mingzhu Ye, Dan Liu, Wenchao Zhou, Tian Zeng, Sili He, Yukun Li.

  Ovarian cancer (OC) is a gynecological malignancy that results in a global threat to women's lives. Lactic acid, a key metabolite produced from the glycolytic metabolism of glucose molecules, is correlated with tumor immune infiltration and platinum resistance. In our previous study, we found that endothelial cell-specific molecule 1 (ESM1) plays a key role in OC progression. This study revealed that lactate could upregulate ESM1, which enhances SCD1 to attenuate the antitumor CD8+ T-cell response. ESM1 and SCD1 expression levels were significantly greater in OC patients with high lactic acid levels than in those with low lactic acid levels. Further mechanistic studies suggested that the Wnt/β-catenin pathway was inactivated after ESM1 knockdown and rescued by SCD1 overexpression. IC50 analysis indicated that the ESM1-SCD1 axis induces the resistance of OC cells to platinum agents, including cisplatin, carboplatin, and oxaliplatin, by upregulating P-gp. In conclusion, our study indicated that the induction of SCD1 by lactic acid-induced ESM1 can impede the CD8+ T-cell response against tumors and promote resistance to cisplatin by activating the Wnt/β-catenin pathway in ovarian cancer. Consequently, targeting ESM1 may have considerable therapeutic potential for modulating the tumor immune microenvironment and enhancing drug sensitivity in OC patients.

Keywords:  CD8 T cell; Cisplatin resistance; ESM1; Lactate; Ovarian cancer

DOI:  https://doi.org/10.1016/j.intimp.2024.112461
Cell Biochem Funct. 2024 Jun;42(4): e4077

Extracellular vesicles originating from steatotic hepatocytes promote hepatic stellate cell senescence via AKT/mTOR signaling.

Zongmei Wu, Mengmeng Xia, Junyu Wang, Magnolia Martinez Aguilar, Manon Buist-Homan, Han Moshage.

  The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing rapidly due to the obesity epidemic. In the inflammatory stages of MASLD (MASH), activation of hepatic stellate cells (HSCs) leads to initiation and progression of liver fibrosis. Extracellular vesicles (EVs) are released from all cell types and play an important role in intercellular communication. However, the role of EVs released from hepatocytes in the context of MASLD is largely unknown. Therefore, the present study aimed to investigate the role of EVs derived from both normal and steatotic (free fatty acid-treated) hepatocytes on the phenotype of HSCs via the senescence pathway. Primary rat hepatocytes were treated with free fatty acids (FFAs: oleic acid and palmitic acid). EVs were collected by ultracentrifugation. EVs markers and HSCs activation and senescence markers were assessed by Western blot analysis, qPCR and cytochemistry. Reactive oxygen species (ROS) production was assessed by fluorescence assay. RNA profiles of EVs were evaluated by sequencing. We found that EVs from hepatocytes treated with FFAs (FFA-EVs) inhibit collagen type 1 and α-smooth muscle actin expression, increase the production of ROS and the expression of senescence markers (IL-6, IL-1β, p21 and senescence-associated β-galactosidase activity) in early activating HSCs via the AKT-mTOR pathway. Sequencing showed differentially enriched RNA species between the EVs groups. In conclusion, EVs from FFA-treated hepatocytes inhibit HSC activation by inducing senescence via the AKT-mTOR signaling pathway. Determining the components in EVs from steatotic hepatocytes that induce HSC senescence may lead to the identification of novel targets for intervention in the treatment of MASLD in the future.

Keywords:  AKT/mTOR signaling; MASLD; extracellular vesicles; hepatic stellate cells; miRNAs; senescence

DOI:  https://doi.org/10.1002/cbf.4077
Inflammation. 2024 Jun 17.

AMPK Regulates M1 Macrophage Polarization through the JAK2/STAT3 Signaling Pathway to Attenuate Airway Inflammation in Obesity-Related Asthma.

Jiahui Lei, Zhenhui Shu, He Zhu, Limin Zhao.

  Abstract-Obesity-related asthma is primarily characterized by nonallergic inflammation, with pathogenesis involving oxidative stress, metabolic imbalance, and immunoinflammatory mechanisms. M1 macrophages, which predominantly secrete pro-inflammatory factors, mediate insulin resistance and systemic metabolic inflammation in obese individuals. Concurrently, adenosine monophosphate-activated protein kinase (AMPK) serves as a critical regulator of intracellular energy metabolism and is closely associated with macrophage activation. However, their specific roles and associated mechanisms in obesity-related asthma remain to be explored. In this study, we investigated the macrophage polarization status and potential interventional mechanisms through obesity-related asthmatic models and lipopolysaccharide (LPS) -treated RAW264.7 cell with a comprehensive series of evaluations, including HE, PAS and Masson staining of lung histopathology, immunohistochemical staining, immunofluorescence technology, qRT-PCR, Western Blot, and ELISA inflammatory factor analysis. The results revealed M1 macrophage polarization in obesity-related asthmatic lung tissue alongside downregulation of AMPK expression. Under LPS stimulation, exogenous AMPK activation attenuated M1 macrophage polarization via the Janus kinase 2/ signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Additionally, in obesity-related asthmatic mice, AMPK activation was found to alleviate airway inflammation by regulating M1 macrophage polarization, the mechanism closely associated with the JAK2/STAT3 pathway. These findings not only advance our understanding of macrophage polarization in obesity-related asthma, but also provide new therapeutic targets for its treatment.

Keywords:  AMPK; Airway inflammation; JAK2/STAT3; M1 macrophage polarization; Obesity-related asthma

DOI:  https://doi.org/10.1007/s10753-024-02070-x
Mol Cancer Res. 2024 Jun 18.

Lactate induces tumor progression via LAR motif-dependent Yin-Yang 1 degradation.

Shujuan Du, Xiaoting Chen, Xiao Han, Yuyan Wang, Dan Yu, Ying Li, Caixia Zhu, Yin Tong, Shujun Gao, Junwen Wang, Fang Wei, Qiliang Cai.

Metabolic reprogramming of aerobic glycolysis contributes to tumorigenesis. High plasma lactate is a critical regulator in the development of many human malignancies; however, the underlying molecular mechanisms of cancer progression in the response to lactate (LA) remain elusive. Here we show that reduction of Yin-Yang 1 (YY1) expression correlated with high LA commonly occurs in various cancer cell types, including B-lymphoma and cervical cancer. Mechanistically, LA induces YY1 nuclear export and degradation via HSP70-mediated autophagy adjacent to mitochondria in a Histidine-rich LAR (LA-responsive) motif-dependent manner. Mutation of the LAR motif blocks LA-mediated YY1 cytoplasmic accumulation and in turn enhances cell apoptosis. Furthermore, low expression of YY1 promotes the colony formation, invasion, angiogenesis and growth of cancer cells in response to LA in vitro and in vivo using a murine xenograft model. Taken together, our findings reveal that a key lactate-responsive` element and may serve as therapeutic target for intervening cancer progression. Implications: We have shown lactate can induce YY1 degradation via its Histidine-rich LAR motif, and low expression of YY1 promotes cancer cell progression in response to lactate, leading to better prediction of YY1-targeting therapy.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0583
J Clin Invest. 2024 Jun 18. pii: e176136. [Epub ahead of print]

Inhibition of the eukaryotic initiation factor-2-α kinase PERK decreases risk of autoimmune diabetes in mice.

Charanya Muralidharan, Fei Huang, Jacob R Enriquez, Jiayi E Wang, Jennifer B Nelson, Titli Nargis, Sarah C May, Advaita Chakraborty, Kayla T Figatner, Svetlana Navitskaya, Cara M Anderson, Veronica Calvo, David Surguladze, Mark J Mulvihill, Xiaoyan Yi, Soumyadeep Sarkar, Scott A Oakes, Bobbie-Jo M Webb-Robertson, Emily K Sims, Kirk A Staschke, Decio L Eizirik, Ernesto S Nakayasu, Michael E Stokes, Sarah A Tersey, Raghavendra G Mirmira.

  Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2α. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing beta cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α kinase PERK, a common component of the UPR and ISR, reversed the mRNA translation block in stressed human islets and delayed the onset of diabetes, reduced islet inflammation, and preserved β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-βH1 human β cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.

Keywords:  Beta cells; Diabetes; Endocrinology; Pharmacology

DOI:  https://doi.org/10.1172/JCI176136
Med Oncol. 2024 Jun 20. 41(7): 182

Interleukin-6 serves as a critical factor in various cancer progression and therapy.

Asma'a H Mohamed, Abdulrahman T Ahmed, Waleed Al Abdulmonem, Dmitry Olegovich Bokov, Alaa Shafie, Hussein Riyadh Abdul Kareem Al-Hetty, Chou-Yi Hsu, Mohammed Alissa, Shahid Nazir, Mohammad Chand Jamali, Mustafa Mudhafar.

  Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays a crucial role in host immune defense and acute stress responses. Moreover, it modulates various cellular processes, including proliferation, apoptosis, angiogenesis, and differentiation. These effects are facilitated by various signaling pathways, particularly the signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2). However, excessive IL-6 production and dysregulated signaling are associated with various cancers, promoting tumorigenesis by influencing all cancer hallmarks, such as apoptosis, survival, proliferation, angiogenesis, invasiveness, metastasis, and notably, metabolism. Emerging evidence indicates that selective inhibition of the IL-6 signaling pathway yields therapeutic benefits across diverse malignancies, such as multiple myeloma, prostate, colorectal, renal, ovarian, and lung cancers. Targeting key components of IL-6 signaling, such as IL-6Rs, gp130, STAT3, and JAK via monoclonal antibodies (mAbs) or small molecules, is a heavily researched approach in preclinical cancer studies. The purpose of this study is to offer an overview of the role of IL-6 and its signaling pathway in various cancer types. Furthermore, we discussed current preclinical and clinical studies focusing on targeting IL-6 signaling as a therapeutic strategy for various types of cancer.

Keywords:  Cancer; IL-6; Inflammatory cytokines; STAT3; Targeted therapy

DOI:  https://doi.org/10.1007/s12032-024-02422-5
Int J Mol Sci. 2024 May 23. pii: 5691. [Epub ahead of print]25(11):

Ovarian Cancer Cell-Conditioning Medium Induces Cancer-Associated Fibroblast Phenoconversion through Glucose-Dependent Inhibition of Autophagy.

Alessandra Ferraresi, Carlo Girone, Chinmay Maheshwari, Letizia Vallino, Danny N Dhanasekaran, Ciro Isidoro.

  One aspect of ovarian tumorigenesis which is still poorly understood is the tumor-stroma interaction, which plays a major role in chemoresistance and tumor progression. Cancer-associated fibroblasts (CAFs), the most abundant stromal cell type in the tumor microenvironment, influence tumor growth, metabolism, metastasis, and response to therapy, making them attractive targets for anti-cancer treatment. Unraveling the mechanisms involved in CAFs activation and maintenance is therefore crucial for the improvement of therapy efficacy. Here, we report that CAFs phenoconversion relies on the glucose-dependent inhibition of autophagy. We show that ovarian cancer cell-conditioning medium induces a metabolic reprogramming towards the CAF-phenotype that requires the autophagy-dependent glycolytic shift. In fact, 2-deoxy-D-glucose (2DG) strongly hampers such phenoconversion and, most importantly, induces the phenoreversion of CAFs into quiescent fibroblasts. Moreover, pharmacological inhibition (by proline) or autophagy gene knockdown (by siBECN1 or siATG7) promotes, while autophagy induction (by either 2DG or rapamycin) counteracts, the metabolic rewiring induced by the ovarian cancer cell secretome. Notably, the nutraceutical resveratrol (RV), known to inhibit glucose metabolism and to induce autophagy, promotes the phenoreversion of CAFs into normal fibroblasts even in the presence of ovarian cancer cell-conditioning medium. Overall, our data support the view of testing autophagy inducers for targeting the tumor-promoting stroma as an adjuvant strategy to improve therapy success rates, especially for tumors with a highly desmoplastic stroma, like ovarian cancer.

Keywords:  autophagy; cancer cell secretome; hexokinase 2; metabolic reprogramming; ovarian cancer; resveratrol; reverse Warburg effect; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25115691
Clin Nutr. 2024 Jun 07. pii: S0261-5614(24)00197-3. [Epub ahead of print]43(8): 1685-1693

Growth differentiation factor 15 (GDF15) levels are associated with malnutrition in acutely admitted older adults.

Rikke Lundsgaard Nielsen, Olivia Bornæs, Esben Iversen, Louise Westberg Strejby Christensen, Thomas Kallemose, Baker Jawad, Henrik Højgaard Rasmussen, Tina Munk, Trine Meldgaard Lund, Ove Andersen, Morten Baltzer Houlind, Aino Leegaard Andersen, Juliette Tavenier.

   BACKGROUND AND AIMS: The aging process is often accompanied by high risk of malnutrition and elevated levels of growth differentiation factor 15 (GDF15). GDF15 is an increasingly recognized biomarker for regulation of metabolism, but few studies have investigated the connection between GDF15 and malnutrition in older age and how it relates to other features of aging such as decreased appetite and physical function. Therefore, we investigated the associations between GDF15 levels and nutritional status, appetite, and physical function in acutely admitted older adults.
METHODS: Plasma GDF15 levels were measured using immunoassays in 302 older adults (≥65 years) admitted to the emergency department (ED). Nutritional status was evaluated with the Mini Nutritional Assessment Short-Form (MNA®-SF), appetite was evaluated with the Simplified Nutritional Appetite Questionnaire (SNAQ), and physical function was evaluated with handgrip strength (HGS), 30-s chair stand test (30s-RSS), and gait speed (GS). Associations between GDF15 and each outcome was determined by logistic regression adjusted for age, sex, and C-reactive protein (CRP).
RESULTS: Each doubling in plasma GDF15 level was associated with an adjusted odds ratio (OR) (95% confidence interval) of 1.59 (1.10-2.29, P = 0.01) for risk of malnutrition compared to normal nutrition and 1.19 (0.85-1.69, P = 0.3)) for malnutrition compared to risk of malnutrition. Each doubling in GDF15 was associated with an adjusted OR of 1.63 (1.21-2.23)) for having poor appetite, 1.46 (1.07-1.99) for having low HGS, 1.74 (1.23-2.51) for having low 30s-RSS, and 1.99 (1.39-2.94) for having low GS.
CONCLUSION: Among older adults admitted to the ED, higher GDF15 levels were significantly associated with malnutrition, poor appetite, and low physical function independent of age, sex, and CRP.

Keywords:  Appetite; Chronic inflammation; Emergency care; Malnutrition; Older adults; Physical function

DOI:  https://doi.org/10.1016/j.clnu.2024.06.005
Science. 2024 Jun 21. 384(6702): eadf1329

Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.

Divij Mathew, Melina E Marmarelis, Caitlin Foley, Joshua M Bauml, Darwin Ye, Reem Ghinnagow, Shin Foong Ngiow, Max Klapholz, Soyeong Jun, Zhaojun Zhang, Robert Zorc, Christiana W Davis, Maximillian Diehn, Josephine R Giles, Alexander C Huang, Wei-Ting Hwang, Nancy R Zhang, Adam J Schoenfeld, Erica L Carpenter, Corey J Langer, E John Wherry, Andy J Minn.

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.

DOI: https://doi.org/10.1126/science.adf1329