bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024‒09‒15
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Palmitic acid promotes miRNA release from adipocyte exosomes by activating NF-κB/ER stress.
  2. Endothelial metabolic control of insulin sensitivity through resident macrophages.
  3. CAF-induced physical constraints controlling T cell state and localization in solid tumours.
  4. Roles of extracellular vesicles derived from healthy and obese adipose tissue in inter-organ crosstalk and potential clinical implication.
  5. Cancer cell - Fibroblast crosstalk via HB-EGF, EGFR, and MAPK signaling promotes the expression of macrophage chemo-attractants in squamous cell carcinoma.
  6. TCEB2/HIF1A signaling axis promotes chemoresistance in ovarian cancer cells by enhancing glycolysis and angiogenesis.
  7. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation.
  1. Nutr Diabetes. 2024 Sep 13. 14(1): 75
    Palmitic acid promotes miRNA release from adipocyte exosomes by activating NF-κB/ER stress.
    Menghuan Li, Yanting Hou, Yao Chen, Chaoyue Sun, Maodi Liang, Xiaolong Chu, Xin Wen, Fangyuan Yuan, Chaoling Peng, Cuizhe Wang, Jianxin Xie, Jun Zhang.
      OBJECTIVE: The release of adipose tissue-derived miRNAs is increased under conditions of obesity, but the exact molecular mechanisms involved have not been elucidated. This study investigated whether obesity-induced increases in palmitic acid (PA) content could activate the NF-κB/endoplasmic reticulum stress (ER stress) pathway and promote the expression and release of exosomal miRNAs in adipocytes.METHODS: Abdominal adipose tissue and serum samples were collected from normal weight individuals and people with obesity to clarify the correlation of serum PA content with NF-κB/ER stress and the release of exosomal miRNAs. NF-κB and ER stress were blocked in obese mice and in vitro cultured adipocytes to demonstrate the molecular mechanisms by which PA promotes the release of exosomal miRNAs.The morphology, particle size and distribution of the exosomes were observed via transmission electron microscopy and NTA.
    RESULTS: Accompanied by increased serum PA levels, the NF-κB/ER stress pathway was activated in the adipose tissue of people with obesity and in high-fat diet (HFD)-induced obese mice; moreover, the levels of miRNAs in both adipose tissue and serum were increased. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reduced the levels of miRNAs in abdominal adipose tissue and serum, decreased blood glucose levels, and improved glucose tolerance and insulin sensitivity in obese mice. In 3T3-L1 adipocytes, high concentrations of PA activated the NF-κB/ER stress pathway and increased the expression and release of miRNAs in exosomes. P-p65 (Bay11-7082) and ER stress (TUDCA) blockers significantly reversed the increased release exosomal miRNAs cause by PA.
    CONCLUSIONS: Obesity-induced increases in PA content increase the expression and release of miRNAs in adipocyte exosomes by activating the NF-κB/ER stress pathway.
    DOI:  https://doi.org/10.1038/s41387-024-00334-x
  2. Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]
    Endothelial metabolic control of insulin sensitivity through resident macrophages.
    Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.
      Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
    Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
  3. Nat Rev Cancer. 2024 Sep 09.
    CAF-induced physical constraints controlling T cell state and localization in solid tumours.
    Ludovica Arpinati, Giulia Carradori, Ruth Scherz-Shouval.
      Solid tumours comprise cancer cells that engage in continuous interactions with non-malignant cells and with acellular components, forming the tumour microenvironment (TME). The TME has crucial and diverse roles in tumour progression and metastasis, and substantial efforts have been dedicated into understanding the functions of different cell types within the TME. These efforts highlighted the importance of non-cell-autonomous signalling in cancer, mediating interactions between the cancer cells, the immune microenvironment and the non-immune stroma. Much of this non-cell-autonomous signalling is mediated through acellular components of the TME, known as the extracellular matrix (ECM), and controlled by the cells that secrete and remodel the ECM - the cancer-associated fibroblasts (CAFs). In this Review, we delve into the complex crosstalk among cancer cells, CAFs and immune cells, highlighting the effects of CAF-induced ECM remodelling on T cell functions and offering insights into the potential of targeting ECM components to improve cancer therapies.
    DOI:  https://doi.org/10.1038/s41568-024-00740-4
  4. Front Endocrinol (Lausanne). 2024 ;15 1409000
    Roles of extracellular vesicles derived from healthy and obese adipose tissue in inter-organ crosstalk and potential clinical implication.
    Yue Han, Sheng Ye, Bowen Liu.
      Extracellular vesicles (EVs) are nanovesicles containing bioactive molecules including proteins, nucleic acids and lipids that mediate intercellular and inter-organ communications, holding promise as potential therapeutics for multiple diseases. Adipose tissue (AT) serves as a dynamically distributed energy storage organ throughout the body, whose accumulation leads to obesity, a condition characterized by infiltration with abundant immune cells. Emerging evidence has illustrated that EVs secreted by AT are the novel class of adipokines that regulate the homeostasis between AT and peripheral organs. However, most of the studies focused on the investigations of EVs derived from adipocytes or adipose-derived stem cells (ADSCs), the summarization of functions in cellular and inter-organ crosstalk of EVs directly derived from adipose tissue (AT-EVs) are still limited. Here, we provide a systemic summary on the key components and functions of EVs derived from healthy adipose tissue, showing their significance on the tissue recovery and metabolic homeostasis regulation. Also, we discuss the harmful influences of EVs derived from obese adipose tissue on the distal organs. Furthermore, we elucidate the potential applications and constraints of EVs from healthy patients lipoaspirates as therapeutic agents, highlighting the potential of AT-EVs as a valuable biological material with broad prospects for future clinical use.
    Keywords:  adipose tissue; clinical implication; extracellular vesicles; inter-organ communication; obesity
    DOI:  https://doi.org/10.3389/fendo.2024.1409000
  5. iScience. 2024 Sep 20. 27(9): 110635
    Cancer cell - Fibroblast crosstalk via HB-EGF, EGFR, and MAPK signaling promotes the expression of macrophage chemo-attractants in squamous cell carcinoma.
    Giovanni Giangreco, Antonio Rullan, Yutaka Naito, Dhruva Biswas, Yun-Hsin Liu, Steven Hooper, Pablo Nenclares, Shreerang Bhide, Maggie Chon U Cheang, Probir Chakravarty, Eishu Hirata, Charles Swanton, Alan Melcher, Kevin Harrington, Erik Sahai.
      Interactions between cells in the tumor microenvironment (TME) shape cancer progression and patient prognosis. To gain insights into how the TME influences cancer outcomes, we derive gene expression signatures indicative of signaling between stromal fibroblasts and cancer cells, and demonstrate their prognostic significance in multiple and independent squamous cell carcinoma cohorts. By leveraging information within the signatures, we discover that the HB-EGF/EGFR/MAPK axis represents a hub of tumor-stroma crosstalk, promoting the expression of CSF2 and LIF and favoring the recruitment of macrophages. Together, these analyses demonstrate the utility of our approach for interrogating the extent and consequences of TME crosstalk.
    Keywords:  Cancer; Microenvironment; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.110635
  6. Eur J Med Res. 2024 Sep 11. 29(1): 456
    TCEB2/HIF1A signaling axis promotes chemoresistance in ovarian cancer cells by enhancing glycolysis and angiogenesis.
    Zhuo Deng, Bin Li, Wenzhi Wang, Wei Xia, Lu Zhang, Lihong Chen, Wen Jin.
      Ovarian cancer is an extremely malignant gynaecological tumour with a poor patient prognosis and is often associated with chemoresistance. Thus, exploring new therapeutic approaches to improving tumour chemosensitivity is important. The expression of transcription elongation factor B polypeptide 2 (TCEB2) gene is reportedly upregulated in ovarian cancer tumour tissues with acquired resistance, but the specific mechanism involved in tumour resistance remains unclear. In this study, we found that TCEB2 was abnormally highly expressed in cisplatin-resistant tumour tissues and cells. TCEB2 silencing also inhibited the growth and glycolysis of SKOV-3/cisplatin (DDP) and A2780/DDP cells. We further incubated human umbilical vein endothelial cells (HUVECs) with culture supernatants from cisplatin-resistant cells having TCEB2 knockdown. Results revealed that the migration, invasion, and angiogenesis of HUVECs were significantly inhibited. Online bioinformatics analysis revealed that the hypoxia-inducible factor-1A (HIF-1A) protein may bind to TCEB2, and TCEB2 silencing inhibited SKOV-3/DDP cell growth and glycolysis by downregulating HIF1A expression. Similarly, TCEB2 promoted HUVEC migration, invasion, and angiogenesis by upregulating HIF1A expression. In vivo experiments showed that TCEB2 silencing enhanced the sensitivity of ovarian cancer nude mice to cisplatin and that TCEB2 knockdown inhibited the glycolysis and angiogenesis of tumour cells. Our findings can serve as a reference for treating chemoresistant ovarian cancer.
    Keywords:  Angiogenesis; Chemoresistance; Glycolysis; HIF1A; Ovarian cancer; TCEB2
    DOI:  https://doi.org/10.1186/s40001-024-02050-9
  7. Cell Metab. 2024 Aug 29. pii: S1550-4131(24)00332-2. [Epub ahead of print]
    SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation.
    Wenhui Liu, Danming You, Jiayang Lin, Huren Zou, Lei Zhang, Shenjian Luo, Youwen Yuan, Zhiyi Wang, Jingwen Qi, Weiwei Wang, Xueru Ye, Xiaoyu Yang, Yajuan Deng, Fei Teng, Xiaojun Zheng, Yuhao Lin, Zhiwei Huang, Yan Huang, Zhi Yang, Xuan Zhou, Yanan Zhang, Ruxin Chen, Lingling Xu, Jin Li, Wei Yang, Huijie Zhang.
      During the progression of metabolic dysfunction-associated steatohepatitis (MASH), the accumulation of auto-aggressive CD8+ T cells significantly contributes to liver injury and inflammation. Empagliflozin (EMPA), a highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), exhibits potential therapeutic benefits for liver steatosis; however, the underlying mechanism remains incompletely elucidated. Here, we found that EMPA significantly reduced the hepatic accumulation of auto-aggressive CD8+ T cells and lowered granzyme B levels in mice with MASH. Mechanistically, EMPA increased β-hydroxybutyric acid by promoting the ketogenesis of CD8+ T cells via elevating 3-hydroxybutyrate dehydrogenase 1 (Bdh1) expression. The β-hydroxybutyric acid subsequently inhibited interferon regulatory factor 4 (Irf4), which is crucial for CD8+ T cell activation. Furthermore, the ablation of Bdh1 in T cells aggravated the manifestation of MASH and hindered the therapeutic efficacy of EMPA. Moreover, a case-control study also showed that SGLT2 inhibitor treatment repressed CD8+ T cell infiltration and improved liver injury in patients with MASH. In summary, our study indicates that SGLT2 inhibitors can target CD8+ T cells and may be an effective strategy for treating MASH.
    Keywords:  BDH1; CD8(+) T cell; SGLT2 inhibitor; ketogenesis; metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.005
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