bims-meluca 2025-05-18 papers

Cancer Res. 2025 May 14.

Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression.

Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). Here, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared to non-smokers. Exposure of lung cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of cancer cells through succinylation of GAPDH to drive NSCLC progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3525

Oncogene. 2025 May 14.

Derlin-3 manipulates the endoplasmic reticulum stress and IgG4 secretion of plasma cells in lung adenocarcinoma.

Lanlan Lin, Luyang Chen, Guofu Lin, Xiaohui Chen, Linlin Huang, Jiansheng Yang, Shaohua Chen, Ronghang Lin, Dongyong Yang, Fei He, Danwen Qian, Yiming Zeng, Yuan Xu.

Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. In the present study, we found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting Hrd1/p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo. Our results indicated that Derlin-3 could shape TME via ER stress to harness immune function, which might serve as a promising immunotherapeutic target in LUAD.

DOI: https://doi.org/10.1038/s41388-025-03435-8

Front Cell Infect Microbiol. 2025 ;15 1513270

Integrative multi-omics analysis of the microbiome and metabolome in bronchoalveolar lavage fluid from patients with early-stage lung cancer.

Jiajun Xie, Nengyang Zhu, Weiguo Xu.

Lung cancer is a significant health concern that poses a considerable threat to human health and quality of life. In order to enhance the prognosis of patients with lung cancer, we conducted a combined analysis of 16S rDNA gene sequencing of alveolar lavage fluid and LC-MS metabolomics research, with the objective of identifying biomarkers in patients with early-stage lung cancer presenting as SPN. A comparison of the benign nodule group and the early-stage lung cancer patients revealed that the phylum-level Bacteroidetes and the genus-level Chryseobacterium and Delftia were more abundant in the latter group. Additionally, the Fusobacteriales might serve as a predictive marker for the diagnosis of early-stage lung cancer. In the context of metabolomics, the early-stage lung cancer was found to be characterised by elevated levels of specific metabolites, including Alternariol, dTMP, Oxymatrine, Gedunin, PC 36:4. Conversely, reductions in other metabolites, such as LPC O-24:0, PC 18:2_18:3, PC 19:2_19:2, Cholecalciferol and T-2 Triol, were also observed. Correlation analyses demonstrated that alveolar lavage microorganisms were closely associated with differential metabolites. Specifically, reductions in Cholecalciferol were associated with a variety of high-abundance flora and involved in vitamin digestion and absorption pathways. Furthermore, reductions in cholecalciferol may serve as a robust predictor of early-stage lung cancer. These findings provide new predictive biomarkers for early-stage lung cancer manifested by SPN, which is clinically important and requires further study of the potential mechanisms of action and function of the targets.

Keywords: 16S rDNA; LC-MS; SPN; bronchoalveolar lavage fluid (BALF); lung cancer

DOI: https://doi.org/10.3389/fcimb.2025.1513270

Cancer Res. 2025 May 14.

MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.

Tianyu Qu, Lei Song, Jiali Xu, Xiyi Lu, Dandan Yin, Jiali Dai, Chen Zhang, Renhua Guo, Erbao Zhang.

Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in NSCLC patient samples and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted post transcriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer binding factor 3 (ILF3), thus interacting with the 3'UTR of glutamate dehydrogenase 1 (GLUD1) to post-transcriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3748

Cell Rep. 2025 May 10. pii: S2211-1247(25)00460-7. [Epub ahead of print]44(5): 115689

Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.

Jeremy B Ducharme, Daria Neyroud, Martin M Schonk, Miguel A Gutierrez-Monreal, Zhiguang Huo, Haley O Tucker, Karyn A Esser, Sarah M Judge, Andrew R Judge.

Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal-muscle clock in response to cancer that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal-muscle circadian transcriptome toward pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal-muscle circadian transcriptome, which may contribute to muscle wasting and the development of cachexia.

Keywords: CP: Cancer; ChIP-seq; RNA-seq; cancer cachexia; circadian rhythm; inflammation; metabolism; muscle atrophy; muscle clock; pancreatic cancer; skeletal muscle

DOI: https://doi.org/10.1016/j.celrep.2025.115689

Cell Commun Signal. 2025 May 11. 23(1): 220

Dual inhibition of GTP-bound KRAS and mTOR in lung adenocarcinoma and squamous cell carcinoma harboring KRAS G12C.

Masaoki Ito, Yoshihiro Miyata, Shoko Hirano, Nagisa Morihara, Misako Takemoto, Fumiko Irisuna, Kei Kushitani, Kenichi Suda, Junichi Soh, Yukio Takeshima, Yasuhiro Tsutani, Morihito Okada.

BACKGROUND: Kirsten rat sarcoma (KRAS) mutations are somatic variants in lung adenocarcinoma. One of the most prevalent mutations, G12C, has led to the clinical approval of targeted inhibitors for advanced stages in lung cancer. Research has increasingly focused on the efficacy of combination therapies that target multiple tumorigenic pathways. Cases harboring KRAS G12C mutation are heterogenous. We explored alternative changes in genetic pathways and evaluated the effectiveness of combination therapy using several types of cell lines and KRAS inhibitors.
METHODS: We comprehensively investigated genetic changes induced by KRAS G12C inhibition using RNA sequences and the candidate to inhibit in combination therapy was explored. Three lung cancer cell lines (two adenocarcinoma and one squamous cell carcinoma) and three KRAS G12C inhibitors (AMG 510, MRTX849, and ARS-1620) were used. KRAS G12C and candidate gene were simultaneously inhibited in cell lines and the efficiency of combination therapy was evaluated using clonogenic assays and MTS assay. Pathway activation was assessed via western blotting. A combination index (CI) < 0.8 was considered statistically synergistic.
RESULTS: RNA sequences revealed treatment with two of the three KRAS G12C inhibitors led to a significant increase in mTOR expression across all three cell lines. mTOR was targeted in combination therapy; each KRAS G12C inhibitor and mTOR inhibitor (RAD001) combination exhibited synergism (CI < 0.8) in MTS and clonogenic assays. Single inhibition of mTOR induced activation of guanosine triphosphate (GTP)-RAS, thereby activating the RAS-MEK-ERK and PI3K-AKT-mTOR pathways in WB, suggesting mTOR activation is crucial for KRAS-driving lung cancer. A combination strategy targeting KRAS G12C and mTOR abrogated GTP-RAS, pmTOR (Ser2448), and pERK (Thr202/Tyr204) more efficiently.
CONCLUSIONS: KRAS G12C inhibitor plus RAD001 consistently revealed synergism. Targeting KRAS G12C and mTOR abrogates the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Our data suggests that a combined strategy targeting GTP-bound KRAS G12C and mTOR shows promise for primary lung cancers with KRAS G12C mutations. This approach may also be effective even for lung cancers harboring KRAS G12C mutation but having different profiles.

Keywords: KRAS G12C; mTOR ; AMG 510; ARS-1620; Adagrasib; Combination therapy; Lung adenocarcinoma; MRTX 849; Sotorasib; Squamous cell carcinoma

DOI: https://doi.org/10.1186/s12964-025-02187-y