bims-stacyt 2023-06-11 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–06–11
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing.
Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming.
The role of myokines in cancer: crosstalk between skeletal muscle and tumor.
Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner.
Adipocyte-derived extracellular vesicles: bridging the communications between obesity and tumor microenvironment.
Multitranscript analysis reveals an effect of 2-deoxy-d-glucose on gene expression linked to unfolded protein response and integrated stress response in primary human monocytes and monocyte-derived macrophages.
Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.

bioRxiv. 2023 May 18. pii: 2023.05.15.540823. [Epub ahead of print]

Tumor Cytokine-Induced Hepatic Gluconeogenesis Contributes to Cancer Cachexia: Insights from Full Body Single Nuclei Sequencing.

Ying Liu, Ezequiel Dantas, Miriam Ferrer, Yifang Liu, Aram Comjean, Emma E Davidson, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon.

A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing a Drosophila model, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression of Pepck1 and Pdk , two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia.

DOI: https://doi.org/10.1101/2023.05.15.540823
Commun Biol. 2023 06 03. 6(1): 602

Stress-responsive Gdf15 counteracts renointestinal toxicity via autophagic and microbiota reprogramming.

Navin Ray, Seung Jun Park, Hoyung Jung, Juil Kim, Tamas Korcsmaros, Yuseok Moon.

The integrated stress response (ISR) plays a pivotal role in the cellular stress response, primarily through global translational arrest and the upregulation of cellular adaptation-linked molecules. Growth differentiation factor 15 (Gdf15) is a potent stress-responsive biomarker of clinical inflammatory and metabolic distress in various types of diseases. Herein, we assess whether ISR-driven cellular stress contributes to pathophysiological outcomes by modulating Gdf15. Clinical transcriptome analysis demonstrates that PKR is positively associated with Gdf15 expression in patients with renal injury. Gdf15 expression is dependent on protein kinase R (PKR)-linked ISR during acute renointestinal distress in mice and genetic ablation of Gdf15 aggravates chemical-induced lesions in renal tissues and the gut barrier. An in-depth evaluation of the gut microbiota indicates that Gdf15 is associated with the abundance of mucin metabolism-linked bacteria and their enzymes. Moreover, stress-responsive Gdf15 facilitates mucin production and cellular survival via the reorganization of the autophagy regulatory network. Collectively, ISR-activated Gdf15 counteracts pathological processes via the protective reprogramming of the autophagic network and microbial community, thereby providing robust predictive biomarkers and interventions against renointestinal distress.

DOI: https://doi.org/10.1038/s42003-023-04965-1
BMB Rep. 2023 Jun 09. pii: 5922. [Epub ahead of print]

The role of myokines in cancer: crosstalk between skeletal muscle and tumor.

Se-Young Park, Byeong-Oh Hwang, Na-Young Song.

Loss of skeletal muscle mass is a primary feature of sarcopenia and cancer cachexia. In cancer patients, tumor-derived inflammatory factors promote muscle atrophy via tumor-to-muscle effects, which is closely associated with poor prognosis. During the past decade, skeletal muscle has been considered to function as an autocrine, paracrine, and endocrine organ by releasing numerous myokines. The circulating myokines can modulate pathophysiology in the other organs, as well as in the tumor microenvironment, suggesting myokines function as muscleto-tumor signaling molecules. Here, we highlight the roles of myokines in tumorigenesis, particularly in terms of crosstalk between skeletal muscle and tumor. Better understanding of tumor-to-muscle and muscle-to-tumor effects will shed light on novel strategies for the diagnosis and treatment of cancer.
Nat Commun. 2023 Jun 08. 14(1): 3364

Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner.

Tianyu Tang, Xing Huang, Minghao Lu, Gang Zhang, Xu Han, Tingbo Liang.

Cancer cell metabolism contributes to the establishment of an immunosuppressive tumor microenvironment. Aberrant expression of CD73, a critical enzyme in ATP metabolism, on the cell surface results in the extracellular accumulation of adenosine, which exhibits direct inhibitory effects on tumor-infiltrating lymphocytes. However, little is known about the influence of CD73 on negative immune regulation-associated signaling molecules and transduction pathways inside tumor cells. This study aims to demonstrate the moonlighting functions of CD73 in immunosuppression in pancreatic cancer, an ideal model characterized by complex crosstalk among cancer metabolism, immune microenvironment, and immunotherapeutic resistance. The synergistic effect of CD73-specific drugs in combination with immune checkpoint blockade is observed in multiple pancreatic cancer models. Cytometry by time-of-flight analysis shows that CD73 inhibition reduces tumor-infiltrating Tregs in pancreatic cancer. Tumor cell-autonomous CD73 is found to facilitate Treg recruitment, in which CCL5 is identified as a significant downstream effector of CD73 using integrated proteomic and transcriptomic analyses. CD73 transcriptionally upregulates CCL5 through tumor cell-autocrine adenosine-Adora2a signaling-mediated activation of the p38-STAT1 axis, recruiting Tregs to pancreatic tumors and causing an immunosuppressive microenvironment. Together, this study highlights that CD73-adenosine metabolism transcriptionally controls pancreatic cancer immunosuppression in a tumor-autonomous and -autocrine manner.

DOI: https://doi.org/10.1038/s41467-023-38578-3
Discov Oncol. 2023 Jun 08. 14(1): 92

Adipocyte-derived extracellular vesicles: bridging the communications between obesity and tumor microenvironment.

Chuan Zhou, Yu-Qian Huang, Ming-Xu Da, Wei-Lin Jin, Feng-Hai Zhou.

  By the year 2035 more than 4 billion people might be affected by obesity and being overweight. Adipocyte-derived Extracellular Vesicles (ADEVs/ADEV-singular) are essential for communication between the tumor microenvironment (TME) and obesity, emerging as a prominent mechanism of tumor progression. Adipose tissue (AT) becomes hypertrophic and hyperplastic in an obese state resulting in insulin resistance in the body. This modifies the energy supply to tumor cells and simultaneously stimulates the production of pro-inflammatory adipokines. In addition, obese AT has a dysregulated cargo content of discharged ADEVs, leading to elevated amounts of pro-inflammatory proteins, fatty acids, and carcinogenic microRNAs. ADEVs are strongly associated with hallmarks of cancer (proliferation and resistance to cell death, angiogenesis, invasion, metastasis, immunological response) and may be useful as biomarkers and antitumor therapy strategy. Given the present developments in obesity and cancer-related research, we conclude by outlining significant challenges and significant advances that must be addressed expeditiously to promote ADEVs research and clinical applications.

Keywords:  Adipocyte; Cancer; Extracellular vesicles; Obesity; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-023-00704-4
Biochim Biophys Acta Gen Subj. 2023 Jun 06. pii: S0304-4165(23)00095-8. [Epub ahead of print] 130397

Multitranscript analysis reveals an effect of 2-deoxy-d-glucose on gene expression linked to unfolded protein response and integrated stress response in primary human monocytes and monocyte-derived macrophages.

Y S Tamayo-Molina, Paula A Velilla, Lady Johana Hernández-Sarmiento, Silvio Urcuqui-Inchima.

   BACKGROUND: Glycolytic inhibitor 2-deoxy-d-glucose (2-DG) binds to hexokinase in a non-competitive manner and phosphoglucose isomerase in a competitive manner, blocking the initial steps of the glycolytic pathway. Although 2-DG stimulates endoplasmic reticulum (ER) stress, activating the unfolded protein response to restore protein homeostasis, it is unclear which ER stress-related genes are modulated in response to 2-DG treatment in human primary cells. Here, we aimed to determine whether the treatment of monocytes and monocyte-derived macrophages (MDMs) with 2-DG leads to a transcriptional profile specific to ER stress.
METHODS: We performed bioinformatics analysis to identify differentially expressed genes (DEGs) in previously reported RNA-seq datasets of 2-DG treated cells. RT-qPCR was performed to verify the sequencing data on cultured MDMs.
RESULTS: A total of 95 common DEGs were found by transcriptional analysis of monocytes and MDMs treated with 2-DG. Among these, 74 were up-regulated and 21 were down-regulated. Multitranscript analysis showed that DEGs are linked to integrated stress response (GRP78/BiP, PERK, ATF4, CHOP, GADD34, IRE1α, XBP1, SESN2, ASNS, PHGDH), hexosamine biosynthetic pathway (GFAT1, GNA1, PGM3, UAP1), and mannose metabolism (GMPPA and GMPPB).
CONCLUSIONS: Results reveal that 2-DG triggers a gene expression program that might be involved in restoring protein homeostasis in primary cells.
GENERAL SIGNIFICANCE: 2-DG is known to inhibit glycolysis and induce ER stress; however, its effect on gene expression in primary cells is not well understood. This work shows that 2-DG is a stress inducer shifting the metabolic state of monocytes and macrophages.

Keywords:  Endoplasmic reticulum stress; Human primary cells; Integrated stress response; Protein glycosylation; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bbagen.2023.130397
Proc Natl Acad Sci U S A. 2023 Jun 13. 120(24): e2305245120

Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation.

Sana Hibino, Shotaro Eto, Sho Hangai, Keiko Endo, Sanae Ashitani, Maki Sugaya, Tsuyoshi Osawa, Tomoyoshi Soga, Tadatsugu Taniguchi, Hideyuki Yanai.

  The activation and expansion of T cells that recognize cancer cells is an essential aspect to antitumor immunity. Tumors may escape destruction by the immune system through ectopic expression of inhibitory immune ligands typically exemplified by the PD-L1/PD-1 pathway. Here, we reveal another facet of tumor evasion from T cell surveillance. By secretome profiling of necrotic tumor cells, we identified an oncometabolite spermidine as a unique inhibitor of T cell receptor (TCR) signaling. Mechanistically, spermidine causes the downregulation of the plasma membrane cholesterol levels, resulting in the suppression of TCR clustering. Using syngeneic mouse models, we show that spermidine is abundantly detected in the tumor immune microenvironment (TIME) and that administration of the polyamine synthesis inhibitor effectively enhanced CD8+ T cell-dependent antitumor responses. Further, the combination of the polyamine synthesis inhibitor with anti-PD-1 immune checkpoint antibody resulted in a much stronger antitumor immune response. This study reveals an aspect of immunosuppressive TIME, wherein spermidine functions as a metabolic T cell checkpoint that may offer a unique approach for promoting tumor immunotherapy.

Keywords:  T cell; cancer immunotherapy; cell death; oncometabolite; spermidine

DOI:  https://doi.org/10.1073/pnas.2305245120