bims-meluca 2025-10-12 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–10–12
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Prognostic relevance of TROP2 expression in patients with non-small cell lung cancer receiving immunotherapy.
Plasma Proteome Profiling Identifies Biomarkers and Potential Drug Targets for Non-Small Cell Lung Cancer.
Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma.
Asparagine-linked glycosylation protein 1 (ALG1) promotes aggressive phenotypes of lung adenocarcinoma cells, A549, via modulating N-linked glycosylation and ER-Stress.
ATG4B is required for mTORC1-mediated anabolic activity and is associated with clinical outcomes in non-small cell lung cancer.
Lactic acid promotes non-small cell lung cancer progression by down-regulating hexokinase 1 via histone lactylation: A Mendelian randomization study.

Sci Rep. 2025 Oct 10. 15(1): 35427

Prognostic relevance of TROP2 expression in patients with non-small cell lung cancer receiving immunotherapy.

Naohito Hashimoto, Shota Takei, Kyoichi Kaira, Hisao Imai, Kosuke Hashimoto, Yu Miura, Ayako Shiono, Ou Yamaguchi, Atsuto Mouri, Kunihiko Kobayashi, Mei Hamda, Hiroshi Kagamu.

  Trophoblast surface antigen 2 (TROP2) is strongly expressed in patients with non-small cell lung cancer (NSCLC), and its overexpression is closely associated with a worse prognosis. Recently, a novel TROP2-directed antibody-drug conjugate (ADC) has been developed, and TROP2 has been identified as a therapeutic target for NSCLC. In this study, we investigated whether TROP2 expression can predict the outcome after combined immunotherapy with programmed death-1 (PD-1) blockade plus cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody. The present study included 110 patients with advanced NSCLC who received nivolumab plus ipilimumab (Nivo-Ipi) between 2020 and 2022 at our institution. TROP2 and Ki-67 protein expression were evaluated by immunohistochemistry. Inflammatory and nutritional indices were investigated with several variables, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI), and Glasgow prognostic score. TROP2 was highly expressed in 46 (41.8%) patients, and its overexpression was significantly associated with poor response to Nivo-Ipi therapy. Univariate analysis of all patients identified performance status, liver metastases, bone metastases, NLR, TROP2, PLR, SII, PNI, and ALI as significant predictors of progression-free survival (PFS) and overall survival (OS) after Nivo-Ipi treatment. Multivariate analysis identified TROP2 overexpression as an independent prognostic predictor for PFS and OS. Specifically, TROP2 overexpression was significantly associated with shorter PFS and OS in the subgroups of PD-L1 < 1% or non-adenocarcinoma histology. TROP2 expression could be a significant predictor for outcome after Nivo-Ipi treatment in patients with advanced NSCLC.

Keywords:  CTLA4; Lung cancer; PD-1; Prognosis; Resistance; TROP2

DOI:  https://doi.org/10.1038/s41598-025-19362-3
Int J Med Sci. 2025 ;22(15): 4036-4048

Plasma Proteome Profiling Identifies Biomarkers and Potential Drug Targets for Non-Small Cell Lung Cancer.

Minghui Zhao, Xiaoke Di, Yucui Zhao.

  Non-small cell lung cancer (NSCLC), as one of the most commonly diagnosed cancers globally, requires expedited identification of new drug targets. We conducted proteome-wide MR using genetic data for 4,853 plasma proteins. Summary-level data on lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) were extracted from GWAS meta-analyses (11,273 and 7,426 cases, respectively) and FinnGen cohort (1,590 and 1,510 cases, respectively). We genetically identified eight proteins with a causal role in the etiology of NSCLC. Lower levels of five proteins (CDH17, CXADR, FAM3D, POGLUT3, SFTPB) and higher levels of two proteins (CEACAM5, KLK1) were linked to increased LUAD risk, while higher CD14 levels were associated with elevated LUSC risk. Two proteins, POGLUT3 and SFTPB were validated through Bayesian colocalization. One protein SFTPB was identified using SMR and HEIDI tests. Bidirectional MR found no reverse causality. The primary findings were validated through scRNA-seq, GeneMANIA, GO analysis, druggability assessments and PheWAS analysis. These protein-coding genes are primarily expressed in epithelial cells, macrophages, monocytes, and endothelial cells. Furthermore, CEACAM5, KLK1, and CD14 correspond to existing drugs. These proteins may deepen our comprehension of the etiology and could serve as appealing novel biomarkers and drug targets for NSCLC management.

Keywords:  biomarker; drug target; non-small cell lung cancer.; proteome-wide Mendelian randomization

DOI:  https://doi.org/10.7150/ijms.107109
Nat Commun. 2025 Oct 08. 16(1): 8952

Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.

Vidhi Pareek, Stephen Benkovic.

Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.

DOI: https://doi.org/10.1038/s41467-025-64013-w
Cell Discov. 2025 Oct 07. 11(1): 81

Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma.

Guangyao Shan, Yunyi Bian, Qihai Sui, Jiaqi Liang, Shencheng Ren, Binyang Pan, Haochun Shi, Zhaolin Zheng, Dejun Zeng, Junkan Zhu, Zhencong Chen, Guoshu Bi, Hong Fan, Cheng Zhan.

Lactylation, a lactate-mediated post-translational modification, has garnered significant attention for its pivotal role in epigenetic modulation. However, the intricate interplay between lactylation and ferroptosis in lung adenocarcinoma (LUAD) remains to be fully elucidated. Utilizing metabolomic profiling and comprehensive metabolic library screening, our study uncovers that ferroptosis markedly enhances lactic acid accumulation and subsequent protein lactylation, which in turn confers resistance to ferroptosis in LUAD cells. Functional assays, comprising cell viability tests, lipid peroxidation detection, as well as malondialdehyde and glutathione measurements, collectively reveal that SUMO2-K11 lactylation (SUMO2-K11la), the most prominently elevated lactylation in response to ferroptosis induction, serves as a pivotal factor in determining ferroptosis resistance. Sumoylation proteomics and co-immunoprecipitation assays reveal that SUMO2-K11la impairs the interaction between SUMO2 and ACSL4. Consequently, this disruption facilitates the degradation of ACSL4, thereby disrupting lipid metabolism and effectively mitigating ferroptosis. Furthermore, AARS1 is identified as the lactyltransferase and HDAC1 as the delactylase for SUMO2-K11la. Based on these findings, we develop a cell-penetrating peptide that competitively and specifically inhibits SUMO2-K11la. This peptide significantly potentiates ferroptosis and sensitizes LUAD to cisplatin in xenograft models, while enhancing chemoimmunotherapy responses in spontaneous lung cancer models. Overall, our findings imply that SUMO2-K11la is a pivotal regulator of ferroptosis resistance in LUAD, and suggest a promising strategy to potentiate ferroptosis-based cancer therapies via targeting SUMO2-K11la by the cell-penetrating peptide.

DOI: https://doi.org/10.1038/s41421-025-00829-6
Glycoconj J. 2025 Oct 09.

Asparagine-linked glycosylation protein 1 (ALG1) promotes aggressive phenotypes of lung adenocarcinoma cells, A549, via modulating N-linked glycosylation and ER-Stress.

Kanadit Piriyapairoje, Marta Baro, Aanchal Katoch, Bryce De Muth, Ludovica Villanti, Charupong Saengboonmee, Sopit Wongkham, Joseph N Contessa, Chatchai Phoomak.

  Glycosylation plays a critical role in various biological processes and is essential for cell survival. Aberrant glycosylation has been implicated in numerous diseases, including cancer. Lung cancer remains the leading cause of cancer-related mortality worldwide. The correlation between lung cancer progression and abnormal glycosylation has been demonstrated previously. Asparagine-linked glycosylation protein 1 (ALG1) is a key enzyme involved in the N-linked glycosylation process; however, its role in cancer progression remains unclear. In this study, we investigated the function of ALG1 in lung cancer progression. Analysis of the Cancer Genome Atlas (TCGA) dataset revealed that ALG1 expression was significantly upregulated in lung tumor tissues and was associated with poor patient prognosis. To explore its functional relevance, ALG1 expression was depleted in A549 lung adenocarcinoma cells using CRISPR-Cas9-mediated knockout. Loss of ALG1 led to reduced levels of protein N-linked glycosylation and induced an endoplasmic reticulum (ER)-stress response. Functionally, ALG1 knockout significantly impaired A549 cell proliferation, migration, and invasion, as evidenced by phenotypic assays and molecular markers. Moreover, the extent of glycosylation deficiency was positively correlated with ER-stress activation and inversely associated with cancer cell aggressiveness. These findings suggest that ALG1 promotes lung cancer aggressiveness through the regulation of protein glycosylation and modulation of ER-stress pathways. Overall, this study highlights the potential of ALG1 as a therapeutic target and a prognostic biomarker for lung adenocarcinoma patients.

Keywords:  Asparagine-linked glycosylation 1; Cancer progression; Lung adenocarcinoma; N-glycosylation

DOI:  https://doi.org/10.1007/s10719-025-10198-7
FEBS Open Bio. 2025 Oct 09.

ATG4B is required for mTORC1-mediated anabolic activity and is associated with clinical outcomes in non-small cell lung cancer.

Patrick J Ryan, Bethany C Guerra, Selina Uranga, Jessica M Cardin, Steven E Riechman, Mariana Janini Gomes, James D Fluckey.

  The complex interplay of metabolic signaling networks is critical to the pathophysiology of lung cancer. The anabolic mTORC1 kinase and catabolic process of autophagy are key among these regulatory pathways. While their relationship has long been viewed as a matter of simple inhibition, with mTORC1 as a negative regulator of autophagy, new evidence suggests that this relationship may be more nuanced than previously described. Here, we demonstrate that an autophagy-related, ATG4B, is required for mTORC1 activity and is associated with negative clinical outcomes in non-small cell lung cancer (NSCLC). Targeting ATG4B in vitro suppresses cell proliferation, protein synthesis rates, and mTORC1 signaling in NSCLC cell lines. In contrast, overexpressing the ATG4B protease in healthy models of lung tissue increased mTORC1 kinase activity in healthy lung cell models, indicating that an increase in ATG4B is sufficient to drive cellular anabolic signaling. Finally, we found that ATG4B expression is high in NSCLC patient tumors, is elevated in early-stage cancer, and predicts survival in lung adenocarcinoma patients. Taken together, our results demonstrate that ATG4B is required for anabolic behavior in NSCLC, indicating that the autophagic cascade may be a required input for mTORC1 activity and cellular anabolism in lung cancer. These results have implications for the field of cancer biology more broadly, as they indicate that the far from being a simple target of mTORC1, the autophagic cascade may serve as a requisite input for anabolic signaling, casting new light on the relationship between these processes in cancer pathophysiology.

Keywords:  autophagy; cell signaling; mTORC1; metabolism; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/2211-5463.70138
Medicine (Baltimore). 2025 Oct 03. 104(40): e45065

Lactic acid promotes non-small cell lung cancer progression by down-regulating hexokinase 1 via histone lactylation: A Mendelian randomization study.

Yunpeng Wang, Jijing Zhao, Kaiyu Han.

  The aim of this study was to investigate the effect of lactic acid down-regulation of hexokinase 1 (HK1) on non-small cell lung cancer (NSCLC) through histone lactylation by Mendelian randomization (MR). Genes related to HK1 and NSCLC targets were analyzed using genome-wide association study summary statistics downloaded from public databases. Single-nucleotide polymorphisms associated with HK1 were selected as instrumental variables, and MR analyses were performed using inverse-variance weighted as the primary study method, and MR-Egger, weighted median, simple mode, and weighted mode as complementary methods in order to assess whether HK1 is a protective factor for NSCLC, and to provide further evidence that lactic acid is a risk factor for NSCLC. The results showed that HK1 was significantly and negatively associated with the risk of NSCLC using an inverse-variance weighted method (odds ratio = 0.93, 95% confidence interval = 0.89-0.98, P < .05). This suggests that for every 1-unit increase in genetically predicted HK1 expression, the odds of developing NSCLC decrease by approximately 7%. No significant heterogeneity or directional pleiotropy was detected (MR-Egger intercept P > .05). Leave-one-out sensitivity analysis confirmed the robustness of the findings. This MR study provides genetic evidence that lactic acid may down-regulate HK1 expression via histone lactylation, thereby increasing the risk of NSCLC. However, limitations include the restriction to European ancestry, limited number of instrumental single-nucleotide polymorphisms due to stringent thresholds, and potential residual pleiotropy not captured by current methods. These factors may affect the generalizability and causal interpretability of the findings.

Keywords:  Mendelian randomization; histone lactylation; lactic acid; non-small cell lung cancer

DOI:  https://doi.org/10.1097/MD.0000000000045065