bims-stacyt 2024-09-22 papers

Cell Biol Int. 2024 Sep 16.

Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.

Abhishek Choudhury, Soumya Chatterjee, Shauryabrota Dalui, Pronabesh Ghosh, Altamas Hossain Daptary, Golam Kibria Mollah, Arindam Bhattacharyya.

Cytotoxic CD8+ T cells plays a pivotal role in the adaptive immune system to protect the organism against infections and cancer. During activation and response, T cells undergo a metabolic reprogramming that involves various metabolic pathways, with a predominant reliance on glycolysis to meet their increased energy demands and enhanced effector response. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Recent reports indicates that exosomes may transfer biologically functional molecules to the recipient cells, thereby facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells. This study sought to enlighten possible involvement of cancer-derived exosomes in CD8 + T cell glucose metabolism and discover a regulated signalome as a mechanism of action. We observed reduction in glucose metabolism due to downregulation of AKT/mTOR signalome in activated CD8 + T cells after cancer derived exosome exposure. In-vivo murine breast tumor studies showed better tumor control and antitumor CD8 + T cell glycolysis and effector response after abrogation of exosome release from breast cancer cells. Summarizing, the present study establishes an immune evasion mechanism of breast cancer cell secreted exosomes that will act as a foundation for future precision cancer therapeutics.

Keywords: CD8 + T cells; breast cancer; effector response; exhaustion; exosomes; glycolysis

DOI: https://doi.org/10.1002/cbin.12241

Dev Biol. 2024 Sep 16. pii: S0012-1606(24)00232-X. [Epub ahead of print]517 28-38

JNK Kinase regulates cachexia like syndrome in scribble knockdown tumor model of Drosophila melanogaster.

Rohit Kumar, S Srikrishna.

Cachexia and systemic organ wasting are metabolic syndrome often associated with cancer. However, the exact mechanism of cancer associated cachexia like syndrome still remain elusive. In this study, we utilized a scribble (scrib) knockdown induced hindgut tumor to investigate the role of JNK kinase in cachexia like syndrome. Scrib, a cell polarity regulator, also acts as a tumor suppressor gene. Its loss and mis-localization are reported in various type of malignant cancer-like breast, colon and prostate cancer. The scrib knockdown flies exhibited male lethality, reduced life span, systemic organ wasting and increased pJNK level in hindgut of female flies. Interestingly, knocking down of human JNK Kinase analogue, hep, in scrib knockdown background in hindgut leads to restoration of loss of scrib mediated lethality and systemic organ wasting. Our data showed that scrib loss in hindgut is capable of inducing cancer associated cachexia like syndrome. Here, we firstly report that blocking the JNK signaling pathway effectively rescued the cancer cachexia induced by scrib knockdown, along with its associated gut barrier disruption. These findings have significantly advanced our understanding of cancer cachexia and have potential implications for the development of therapeutic strategies. However, more research is needed to fully understand the complex mechanisms underlying this condition.

Keywords: Cachexia; Cell polarity regulator; Drosophila hindgut; Hep; JNK signaling; Scribble; Systemic organ wasting

DOI: https://doi.org/10.1016/j.ydbio.2024.09.005

Adv Exp Med Biol. 2024 ;1460 273-295

Message Transmission Between Adipocyte and Macrophage in Obesity.

Ayse Basak Engin.

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1β) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.

Keywords: C-C motif chemokine ligand 2 (CCL2/MCP-1); C-C motif chemokine receptor 2 (CCR2); Free fatty acids (FFAs); Hypoxia-inducible factor-1 alpha (HIF-1α); Insulin-like growth factor-1 (IGF1); Interleukin-6 (IL-6); M1 macrophages; M2 macrophages; Monocyte chemoattractant protein-1 (MCP-1); Nucleotide oligomerization domain (NOD)-like receptor (NLR) family protein 3 (NLRP3); Obesity; Toll-like receptor-4 (TLR4); Tumor necrosis factor-alpha (TNF-α); Visceral adipose tissue

DOI: https://doi.org/10.1007/978-3-031-63657-8_9

Sci Adv. 2024 Sep 20. 10(38): eadq5226

NF-κB and TET2 promote macrophage reprogramming in hypoxia that overrides the immunosuppressive effects of the tumor microenvironment.

Carlos de la Calle-Fabregat, Josep Calafell-Segura, Margaux Gardet, Garett Dunsmore, Kevin Mulder, Laura Ciudad, Aymeric Silvin, Joaquim Moreno-Càceres, Ángel L Corbí, Cristina Muñoz-Pinedo, Judith Michels, Sébastien Gouy, Charles-Antoine Dutertre, Javier Rodríguez-Ubreva, Florent Ginhoux, Esteban Ballestar.

Macrophages orchestrate tissue homeostasis and immunity. In the tumor microenvironment (TME), macrophage presence is largely associated with poor prognosis because of their reprogramming into immunosuppressive cells. We investigated the effects of hypoxia, a TME-associated feature, on the functional, epigenetic, and transcriptional reprogramming of macrophages and found that hypoxia boosts their immunogenicity. Hypoxic inflammatory macrophages are characterized by a cluster of proinflammatory genes undergoing ten-eleven translocation-mediated DNA demethylation and overexpression. These genes are regulated by NF-κB, while HIF1α dominates the transcriptional reprogramming, demonstrated through ChIP-seq and pharmacological inhibition. In bladder and ovarian carcinomas, hypoxic inflammatory macrophages are enriched in immune-infiltrated tumors, correlating with better patient prognoses. Coculture assays and cell-cell communication analyses support that hypoxic-activated macrophages enhance T cell-mediated responses. The NF-κB-associated hypomethylation signature is displayed by a subset of hypoxic inflammatory macrophages, isolated from ovarian tumors. Our results challenge paradigms regarding the effects of hypoxia on macrophages and highlight actionable target cells to modulate anticancer immune responses.

DOI: https://doi.org/10.1126/sciadv.adq5226

Metabolism. 2024 Sep 17. pii: S0026-0495(24)00262-2. [Epub ahead of print] 156034

Inter-organ cross-talk in human cancer cachexia revealed by spatial metabolomics.

Na Sun, Tanja Krauss, Claudine Seeliger, Thomas Kunzke, Barbara Stöckl, Annette Feuchtinger, Chaoyang Zhang, Andreas Voss, Simone Heisz, Olga Prokopchuk, Marc E Martignoni, Klaus-Peter Janssen, Melina Claussnitzer, Hans Hauner, Axel Walch.

BACKGROUND: Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx.
METHODS: Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx.
RESULTS: Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs.
CONCLUSIONS: These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.

Keywords: Cancer cachexia patients; Diagnostics of cachexia; Inter-organ cross-talk; Machine learning; Metabolomics classifier; Spatial metabolomics

DOI: https://doi.org/10.1016/j.metabol.2024.156034