bims-meluca 2026-02-08 papers

Nat Commun. 2026 Jan 30.

Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15.

Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1-mutant NSCLC-associated cachexia.

DOI: https://doi.org/10.1038/s41467-026-68702-y

Nat Metab. 2026 Jan 30.

Glucose deprivation drives LIF-dependent lung cancer.

Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of N-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer.

DOI: https://doi.org/10.1038/s42255-025-01437-0

PLoS One. 2026 ;21(2): e0341778

RAF1 as a standalone therapeutic target in KRAS-driven lung adenocarcinoma: No added efficacy from co-targeting ARAF, EGFR, or DDR1.

Laura de-la-Puente-Ovejero, Ana Fernández-Rodríguez, Sarah Francoz, Gonzalo Aizpurua, Lucía Lomba-Riego, Matthias Drosten, Carmen Guerra, Mónica Musteanu, Mariano Barbacid, Sara García-Alonso.

BACKGROUND/OBJECTIVES: KRAS-mutant lung adenocarcinoma remains without effective targeted therapies for most patients, particularly those with non-G12C alleles or resistance to KRASG12C inhibitors. RAF1 is essential for KRAS-driven tumor maintenance through kinase-independent survival functions, making it an attractive candidate for targeted protein degradation. However, the therapeutic impact and safety of co-targeting RAF1 with related kinases remain unclear.
METHODS: We used dual-recombinase genetically engineered mouse models of Kras+/G12V;Trp53-/- lung cancer to evaluate the effects of Raf1 ablation alone or in combination with Araf, Egfr, or Ddr1. Lung tumors were initiated by intranasal Ad5-CMV-FLPo delivery and allowed to reach CT-detectable size before inducing systemic gene deletion via tamoxifen-activated CreERT2. Tumor burden was monitored by longitudinal CT imaging and classified using RECIST-like criteria. Toxicity was assessed by body weight monitoring, histopathology of major organs, and survival analysis.
RESULTS: Raf1 deletion induced robust tumor regression within two months, in more than 60% of lesions. Araf ablation alone or combined with Raf1 did not affect tumor initiation, progression, or regression rates. Similarly, neither genetic nor pharmacological EGFR inhibition (afatinib) improved responses to Raf1 ablation. Ddr1 co-deletion also failed to enhance therapeutic efficacy and slightly reduced response rates. None of the dual-targeting strategies increased systemic toxicity.
CONCLUSIONS: RAF1 is a key, non-redundant vulnerability in KRAS-driven lung adenocarcinoma. Co-targeting ARAF, EGFR, or DDR1 provides no additional therapeutic benefit in established disease. The absence of adverse effects from ARAF co-deletion suggests that RAF1 degraders with partial cross-activity towards ARAF are likely to be safe. These findings provide a strong preclinical rationale for developing RAF1-targeted degradation as a monotherapy for these malignancies.

DOI: https://doi.org/10.1371/journal.pone.0341778

Cureus. 2025 Dec;17(12): e100448

Estimation of Serum C-reactive Protein, Nitric Oxide, Superoxide Dismutase, Glutathione Reductase, and Glutathione Peroxidase Level in Lung Cancer.

Sushant S Dhanavade, Karan Pujari.

Background Oxidative stress and systemic inflammation play critical roles in lung cancer progression. Biomarkers, such as C-reactive protein (CRP), nitric oxide (NO), and key antioxidant enzymes, may contribute to understanding the disease mechanism. Objective The objective of this study is to evaluate serum levels of CRP, NO, superoxide dismutase (SOD), glutathione reductase (GR), and glutathione peroxidase (GPx) in lung cancer patients compared with healthy controls. Methods A case-control study was conducted involving 50 lung cancer patients and 50 age- and sex-matched healthy controls. Serum CRP, NO, SOD, GR, and GPx levels were analyzed using standard biochemical methods, including turbidimetric immunoassay and spectrophotometric techniques. Statistical analysis was performed using SPSS version 26 (IBM Corp., Armonk, NY). A p-value < 0.05 was considered statistically significant. Results Significantly increased serum CRP and NO levels and significantly reduced SOD, GR, and GPx enzyme activities were observed among lung cancer patients compared with controls (p < 0.001). No significant correlations were identified between inflammatory and antioxidant biomarkers. Conclusion The imbalance between elevated inflammatory markers and reduced antioxidant defense suggests enhanced oxidative stress in lung cancer patients. These biomarkers may support clinical assessment and disease monitoring.

Keywords: c-reactive protein; chromosome 21; glutathione peroxidase (gpx); glutathione reductase; interleukin – 1 β; lung cancer; nitric oxide (no)

DOI: https://doi.org/10.7759/cureus.100448

Precis Clin Med. 2026 Mar;9(1): pbag001

Antibiotic exposure impairs the efficacy of first-line chemoimmunotherapy in non-small cell lung cancer through the regulation of gut microbiome and bile acid metabolism.

Hanyan Xu, Jia Yu, Lijing Xia, Xiong Lei, Liwen Zhou, Pengcheng Lin, Shanshan Su, Yuping Li, Chengshui Chen.

Objective: Previous antibiotic therapy is acknowledged to potentially reduce the efficacy of single-agent immune checkpoint inhibitors. Nevertheless, the impact of antibiotics on the results for patients undergoing chemoimmunotherapy remains unclear. This research investigated the influence of antibiotic treatment on the effectiveness of chemoimmunotherapy in advanced non-small cell lung cancer (NSCLC).
Methods: We recorded the characteristics of patients with advanced NSCLC and assessed potential associations between the use of antibiotics and the efficacy of chemoimmunotherapy. A mouse model using Lewis lung carcinoma (LLC) cell lines was developed to assess the effects of antibiotics on the gut microbiome and metabolites. Fecal samples were analyzed using 16S rRNA gene sequencing and ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) methods. Mouse fecal and serum samples and 16 human stool samples were used to validate the identified differentially metabolites. Deoxycholic acid (DCA) was further applied to a LLC mouse model.
Results: This study included 387 NSCLC patients, among whom 86 patients had used antibiotics within the 30 days before the first cycle of chemoimmunotherapy (ATB group), and 301 patients had not used antibiotics (non-ATB group). Notable discrepancies were observed in overall survival and progression-free survival between the two groups, with overall survival recorded at 18.4 months versus 32.0 months, and progression-free survival at 7.6 months versus 13.0 months, in the ATB and non-ATB groups respectively. At the phylum level, the relative abundances of Proteobacteria, Cyanobacteria, and Deinococcus were increased in the ATB mice, while Firmicutes, Bacteroidetes, and Verrucomicrobia were decreased. We detected significant differences in DCA levels in the fecal and serum samples from mice as well as in the fecal sample from humans between the ATB and non-ATB groups. The respective proportions of CD4+ and CD8+ cells were greater in the non-ATB group than in the ATB group, whereas the proportion of Ki67-positive cells was greater in the ATB group. DCA was applied to LLC mice, and DCA along with chemoimmunotherapy effectively inhibited tumor growth in a LLC mouse model. The expression of programmed cell death ligand 1 increased in the DCA group.
Conclusions: Antibiotic exposure is associated with decreased efficacy of chemoimmunotherapy in patients with NSCLC via dysregulation of the gut microbiome and DCA metabolism.

Keywords: antibiotic; chemoimmunotherapy; deoxycholic acid; gut microbiome; metabolism; non-small cell lung cancer

DOI: https://doi.org/10.1093/pcmedi/pbag001

J Biol Chem. 2026 Jan 28. pii: S0021-9258(26)00083-9. [Epub ahead of print] 111213

Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.

Ziwei Wang, Yasuhide Miyamoto, Takehiro Suzuki, Miki Tanaka-Okamoto, Yu Mizote, Naoshi Dohmae, Hideaki Tahara, Naoyuki Taniguchi, Yoichiro Harada.

Mammalian cells exploit diverse metabolic pathways to regulate cell fates during glucose deprivation. We previously reported that glucose deprivation lowers the metabolic activity of mannose pathway that is interconnected with glycolysis, leading to biosynthetic arrest and degradation of the glycan precursors for asparagine-linked glycosylation (N-glycosylation) in the endoplasmic reticulum (ER). However, the cellular role of this sequential metabolic response remains unknown, largely due to metabolic complications caused by glucose deprivation. Here, we genetically engineered cells to separate mannose pathway from glycolysis, allowing precise control of mannose pathway activity by adjusting mannose supply levels instead of changing glucose supply. Moderate decrease in mannose supply severely suppressed N-glycosylation, leading to activation of pro-survival PERK-eIF2 signals. Although further decrease in mannose supply to the minimal levels did not compromise cell survival, it depleted luminal protective glycocalyx of lysosomes and increased a risk of cell death by impairing lysosome integrity. These results indicate that low metabolic flux of glucose into mannose pathway initiates alterations in homeostasis of the ER and lysosomes, at least in part through N-glycosylation defects, leading to cell fate decisions.

Keywords: Cell fate decision; N-glycosylation; endoplasmic reticulum; glucose deprivation; lysosomes

DOI: https://doi.org/10.1016/j.jbc.2026.111213