bims-meluca 2026-04-12 papers

Trends Endocrinol Metab. 2026 Apr 09. pii: S1043-2760(26)00071-8. [Epub ahead of print]

LIFe of the sugar-free party in cancer metabolism.

Tumor cells can thrive in nutrient-scarce environments. Glucose deprivation can trigger adaptive responses that coordinate cell-cell communication within the tumor microenvironment (TME). Recently, Luciano-Mateo et al. demonstrated that glucose withdrawal promotes cancer cell secretion of the cytokine leukemia inhibitory factor (LIF), which exerts protumorigenic effects on the TME.

Keywords: LIF; N-glycosylation; PERK; glucose; lung cancer; metastasis

DOI: https://doi.org/10.1016/j.tem.2026.03.010

J Nanobiotechnology. 2026 Apr 09.

Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.

Xinxin Zhao, Dongmei Lv, Min Wang, Qinyu Guo, Yidi Gao, Wenxiang Fang, Wenlong Zhang, Peipei Wu.

The systemic progression of lung cancer involves a complex interplay between local tumor microenvironment (TME) dynamics and host-level metabolic decline, culminating in cachexia. Extracellular vesicles (EVs), have emerged as critical mediators in this process. This review constructs a comprehensive model of the "EV-metabolic axis" in lung cancer, framing EVs as natural nanocarriers within a systemic communication network that orchestrates a dual pathological process. Locally, EVs remodel the TME to support tumor growth, metastasis, and therapeutic resistance by transferringdiverse metabolic cargoes. Systemically, they transmit catabolic signals to distant adipose and muscle tissues, driving the severe tissue wasting characteristic of cachexia. This integrated perspective reveals the EV-metabolic axis as a central, targetable node in lung cancer pathology. From a nanomedicine perspective, targeting EV biogenesis, cargo loading, or uptake offers a novel, multifaceted therapeutic strategy to simultaneously inhibit tumor growth and mitigate cachexia, heralding a paradigm shift in future lung cancer treatment Scheme 1. This schematic illustrates the tripartite "EV-Metabolic Axis" framework linking local tumor metabolism, systemic EV trafficking, and cachexia development in lung cancer. In the Local Metabolic Axis, primary tumors and stromal cells (CAFs, TAMs, BMSCs) secrete extracellular vesicles (EVs) that reprogram glucose, lipid, and amino acid metabolism via cargoes such as miRNAs, metabolic enzymes, and cytokines - promoting glycolysis, glutamine addiction, ferroptosis resistance, and epithelial-mesenchymal transition (EMT). In the Circulatory System EV Transport Axis, EVs (40-150 nm exosomes, 50-1000 nm ectosomes) traverse biological barriers via membrane fusion, receptor-mediated endocytosis, or ligand-receptor binding, acting as natural nano-carriers. In the Systemic Cachexia Axis, circulating EVs deliver catabolic signals (e.g., miR-21, IL-6, HSP70/90, TGF-β, PTHrP) to distant organs - triggering adipose tissue browning, lipolysis, myofibrillar atrophy, and mitochondrial dysfunction - culminating in cancer-associated cachexia. This integrated axis positions EVs as both biomarkers and therapeutic targets across the nano-bio interface.

Keywords: Extracellular vesicles; Lung cancer cachexia; Metabolic remodeling; Nanomedicine; Tumor microenvironment

DOI: https://doi.org/10.1186/s12951-026-04367-5

Eurasian J Med. 2026 Mar 04. 58(2): 1-6

Dependency of Non-Small Cell Lung Cancer Cells on Glutamine and Glucose Levels in the Presence of Metformin.

Şahika Cıngır Köker, İrem Doğan Turaçlı.

BACKGROUND: Metabolic shift is one of the hallmarks of cancer cells. Due to mutations in oncogenes such as Kirsten Rat Sarcoma Viral Oncogene (KRAS), cancer cells can adapt to stress-induced conditions. One of the adaptations that is commonly observed in non-small cell lung cancer (NSCLC) cells is glutaminolysis, where they exhibit high dependency on the presence of glutamine. Metformin is used for its anti-tumor effects, which inhibit mitochondrial complex I. This study aimed to investigate how glucose and glutamine availability affect the proliferation of three KRAS mutant NSCLC cells under metformin pressure.
METHODS: Using gene expression datasets, it was observed that glutamine was the second most affected metabolite upon metformin-treated A549 cells. Based on this, several 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were done by using high and low glucose conditions having different concentrations of glutamine at different time points. Moreover, metformin was added to the setup to observe the flexibility of the cancer cells in terms of metabolic switches.
RESULTS: Addition of glutamine resulted in a decrease in metformin's antiproliferative effect especially in high glucose conditions at later time points. A significantly higher proliferation rate in low glucose conditions compared to high glucose conditions was observed, which is especially pronounced with the addition of glutamine. These observations were supported by the gene expression analysis of the GSE dataset, which revealed upregulation of apoptosis related genes and downregulation of proliferation-related genes in metformin-treated A549 cells.
CONCLUSION: Taken together, the results highlight the importance of targeting different metabolites and metabolic pathways in cancer therapy. Cite this article as: K.ker ŞC, Tura.lı İD. Dependency of non-small cell lung cancer (NSCLC) cells on glutamine and glucose levels in the presence of metformin. Eurasian J Med. 2026, 58(2), 1018, doi:10.5152/eurasianjmed.2026.251018.

DOI: https://doi.org/10.5152/eurasianjmed.2026.251018

Cell Death Dis. 2026 Apr 10.

Pseudo-senescence induced by palbociclib does not sensitise pleural mesothelioma cells to combinations with senolytics.

Iswarya Sreeram, Sílvia Plans-Marin, Mabel Cruz-Rodríguez, Elisabet Aliagas, Didac Palau-Gallinat, Cristina Muñoz-Pinedo, Ernest Nadal.

Pleural Mesothelioma (PM) is an aggressive neoplasm of the lung pleura with poor survival rates, highlighting the urgent need for novel therapeutic options. The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM. In this study, we observed that palbociclib reduced proliferation, leading to increased cell size, enhanced SA-β-galactosidase activity, and elevated secretion of IL-6 and IL-8 (SASP), all of which are hallmarks of senescence. However, upon drug removal, the cells regrew. To enhance therapeutic efficacy, we attempted to induce cell death in palbociclib-pretreated PM cells with conventional senolytics, such as BH3 mimetics. While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib. We explored the activity of signalling pathways after treatment with palbociclib and identified higher Src and STAT3 phosphorylation, as well as activation of the mTORC1 axis. Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells. In contrast, we found that the chemotherapeutic drug cisplatin induces permanent cell cycle arrest and complete senescence in PM cells. While both drugs increased the phosphorylation of γH2AX, the effects of cisplatin were stronger and more consistent across cell lines. The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models.

DOI: https://doi.org/10.1038/s41419-026-08696-z

Transl Oncol. 2026 Apr 07. pii: S1936-5233(26)00092-6. [Epub ahead of print]67 102755

Circulating low-density neutrophils as biomarkers of resistance to first-line anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC), however reliable predictive biomarkers are lacking. Our group previously reported an association between high levels of circulating low-density neutrophils (LDNs) and resistance to ICI monotherapy. We present updated results, including a validation cohort, proteomic characterization of LDNs, and in vivo experiments exploring mechanisms of resistance.
METHODS: NSCLC patients treated with first line ICI monotherapy (n=60) or combined with chemotherapy (CT+ICI) (n=60) were recruited. LDNs were quantified by flow cytometry and correlated with clinical outcomes. Phenotypes of LDNs and conventional neutrophils were characterised by flow cytometry and quantitative proteomics. Plasma cytokine measurements and in vivo experiments were conducted to assess the role of LDNs in ICI resistance.
RESULTS: High baseline LDN levels were significantly associated with primary resistance to ICI monotherapy, with patients showing an overall response rate (ORR) of 17% vs 50% (p=0.04) and median progression free survival (mPFS) of 2.3 months vs 21.8 months (p < 0.001). No such association was seen in patients treated with CT+ICI, showing a LDN depletion in responders. LDNs exhibited an aged phenotype and distinct proteomic profile. Plasma from high-LDN patients showed elevated myeloid-expansion (M-CSF, IL1β) and inflammatory cytokines (CXCL9, IL-25). Depletion of Gr1+ population enhanced response to ICI and CT+ICI in the Lewis Lung Carcinoma (LLC) model with high LDNs.
CONCLUSION: High baseline LDNs predict resistance to ICI monotherapy in NSCLC and combination with chemotherapy may overcome this resistance. Additional therapeutic strategies targeting LDNs could enhance immunotherapy efficacy.

Keywords: Chemotherapy; Immune checkpoint inhibitors; Immunotherapy resistance; Low-density neutrophils; Myeloid derived suppressor cells; Non-small cell lung cancer

DOI: https://doi.org/10.1016/j.tranon.2026.102755

Cell Death Dis. 2026 Apr 10.

Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.

Dorottya Károlyi, Sólyom Bálint Bótor, Natali Neuhauser, András Rubics, Janka Szinyákovics, Tibor Kovács, Mária Péter, Gábor Balogh, Fergal O'Farrell, Szabolcs Takáts.

Biosynthesis of lipids and fatty acids (FAs) is essential for the normal functioning of cellular processes, and lipid availability determines the progression of multiple malignant tumor types. To date, the roles of individual steps in lipid biosynthesis during tumor growth and their interaction with intracellular signaling pathways are not well understood. Our study demonstrates that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. In vivo tumor cell-specific silencing of components of the neutral lipid biosynthetic apparatus revealed that loss of several enzymes involved in FA and diacylglycerol synthesis inhibited tumor growth. Specifically, acetyl-CoA carboxylase (ACC), which catalyzes the first step of FA synthesis, drives late-stage tumor growth. FA synthesis perturbation led to inactivation of TORC1 (mechanistic Target of Rapamycin Complex 1)-accompanied by activation of the catabolic process autophagy. Moreover, TORC1 activity cannot be fully restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC-deficient tumor cells, but supplementation with ectopic oleic acid can partially increase TORC1 activity and tumor progression. In addition to their metabolic value, the role of FAs in promoting TORC1 gives us new insight into cancer cell dependence on de novo FA synthesis.

DOI: https://doi.org/10.1038/s41419-026-08738-6