bims-meluca 2025-12-07 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–12–07
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Impact of Baseline Body Mass Index on Immunotherapy Outcomes in Patients With Non-small-cell Lung Cancer.
SLBP Promotes Lung Adenocarcinoma Progression by Inhibiting Ferroptosis and Reprogramming Glutamine Metabolism via FADS2 Interaction.
Prognostic role of prognostic nutritional index change in patients with extensive stage small cell lung cancer treated with platinum-based chemotherapy.
KRASG12D/G13D-USP15 axis promotes TGF-β/SMAD signaling and glycolytic flux to accelerate NSCLC pathogenesis.
PPARG-FABP4 regulates PI3K/Akt pathway to promote lung cancer-associated macrophage endoplasmic reticulum stress-mediated CD36 expression and affects lung squamous cell carcinoma metastasis.
Integrative multi-omics identifies endoplasmic reticulum stress-related prognostic biomarkers and CD99-mediated cell-cell communication in lung adenocarcinoma.
Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations.
Toll-like receptor 4 inhibition sensitizes non-small cell lung cancer to radiotherapy.

Anticancer Res. 2025 Dec;45(12): 5579-5586

Impact of Baseline Body Mass Index on Immunotherapy Outcomes in Patients With Non-small-cell Lung Cancer.

Daniel Krejčí, Adam Šubrt, Petr Opálka, Jana Krejčí, Monika Šibalová, Martin Svatoň, Miloslav Pála, Petra Tesařová, Norbert Pauk.

   BACKGROUND/AIM: Assessment of nutritional status plays an important role in treatment of patients with lung cancer. We conducted a real-world study to investigate the potential prognostic value of baseline body mass index (BMI) in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).
PATIENTS AND METHODS: We retrospectively analysed data from 154 patients with advanced NSCLC treated with ICIs in the first or second line. Patients were stratified into two groups: BMI <25 kg/m2 and BMI ≥25 kg/m2. We investigated the impact of BMI on overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and objective response rate (ORR) across the overall population and within prespecified subgroups defined by BMI.
RESULTS: Patients with BMI ≥25 kg/m2 (n=88) had a significantly better ORR compared to those with BMI <25 kg/m2 (n=66): 78.4% vs. 62.1%, p=0.03. There was no significant improvement in PFS, TTF or OS in the overall population. Subgroup analyses showed significant improvement in OS in favour of the BMI ≥25 kg/m2 group in non-smokers, in the subgroup receiving first-line immunotherapy, and in the subgroup with high expression of programmed cell death ligand 1. There was significant improvement in ORR in favour of the BMI ≥25 kg/m2 group in several subgroups. No significant improvements in PFS and TTF in subgroup analyses were observed.
CONCLUSION: Our real-world study suggests that BMI might potentially act as a predictor for ORR in patients with advanced NSCLC treated with ICIs and should be considered in treatment decision-making. Additionally, we also observed a positive trend in OS among this group of patients.

Keywords:  BMI; NSCLC; immune checkpoint inhibitors; immunotherapy

DOI:  https://doi.org/10.21873/anticanres.17892
Exp Cell Res. 2025 Dec 02. pii: S0014-4827(25)00449-5. [Epub ahead of print] 114849

SLBP Promotes Lung Adenocarcinoma Progression by Inhibiting Ferroptosis and Reprogramming Glutamine Metabolism via FADS2 Interaction.

Wei Yan, Pengfei Xu, Dan Xiao, Dong Hong, Huiqun Liu, Yigang Liu, Yaqi Wang, Tanxiu Chen, Anwen Liu.

  SLBP is significantly overexpressed in lung adenocarcinoma (LUAD) and correlates strongly with poor patient prognosis. Functional studies demonstrated that SLBP potently enhances proliferation, invasion, and metastasis of LUAD cells both in vitro and in vivo. Mechanistically, SLBP suppresses ferroptosis-a form of regulated cell death-by modulating key biochemical markers, including GSH, MDA, and Fe2+ levels, and it restores cell viability upon treatment with ferroptosis inducers. RNA-seq and biochemical analyses revealed that SLBP transcriptionally upregulates and stabilizes SLC7A11, a critical ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death. Additionally, immunopurification and mass spectrometry (IP-MS) identified FADS2 as a novel SLBP-interacting partner. SLBP binds to FADS2, promotes its expression, and drives metabolic reprogramming toward glutamine dependency, significantly altering choline and metal ion metabolism. This metabolic shift enhances cellular proliferation under nutrient stress. Crucially, SLBP-mediated proliferation was shown to be functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth without affecting SLBP levels. Collectively, these results uncover SLBP as a multifunctional oncoprotein that promotes LUAD progression through dual mechanisms: inhibiting ferroptosis via SLC7A11 and rewiring glutamine metabolism through FADS2, offering new potential targets for therapeutic intervention.

Keywords:  FADS2; Ferroptosis; Glutamine metabolism; LUAD; SLBP; SLC7A11

DOI:  https://doi.org/10.1016/j.yexcr.2025.114849
BMC Cancer. 2025 Dec 02. 25(1): 1846

Prognostic role of prognostic nutritional index change in patients with extensive stage small cell lung cancer treated with platinum-based chemotherapy.

İrfan Buğday, Mevlüde İnanç, Metin Özkan, Oktay Bozkurt, Ramazan Coşar, Sedat Tarık Fırat, Emel Mutlu, Murat Eser, Ahmet Kürşad Dişli, Muhammet Cengiz.

   BACKGROUND: Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers and is characterized by rapid progression and early metastasis. The prognostic nutritional index (PNI), based on serum albumin and lymphocyte count, has emerged as a potential prognostic biomarker in various cancers.
OBJECTIVE: This study aimed to evaluate the prognostic value of changes in pre- and post-treatment PNI levels in patients with extensive-stage SCLC.
METHODS: A total of 177 treatment-naïve patients with extensive-stage SCLC diagnosed between September 2018 and October 2022 were included. Kaplan-Meier survival analysis and ROC curve analysis were used to assess overall survival (OS) and progression-free survival (PFS) according to PNI categories.
RESULTS: The median OS was 10.3 months and median PFS was 7.5 months in the entire cohort. Patients with persistently low PNI values had the poorest outcomes (median OS 6.4 months, PFS 5.7 months), whereas those with consistently high PNI values had the best prognosis (median OS 14.6 months, PFS 8.4 months; p < 0.001).
CONCLUSIONS: Dynamic changes in PNI are significantly associated with prognosis in extensive-stage SCLC. Patients with low pre- and post-treatment PNI values exhibited worse outcomes, while consistently high PNI predicted better survival. This study is the first to evaluate PNI changes in this patient population.

Keywords:  Extensive stage; Prognostic nutritional index; Small cell lung cancer

DOI:  https://doi.org/10.1186/s12885-025-15246-x
Lung Cancer. 2025 Nov 19. pii: S0169-5002(25)00740-8. [Epub ahead of print]211 108848

KRASG12D/G13D-USP15 axis promotes TGF-β/SMAD signaling and glycolytic flux to accelerate NSCLC pathogenesis.

Ikhlas A Sindi, Abdelghafar M Abu-Elsaoud, Amany I Almars, Nahlah M Ghouth, Sameerah Shaheen, Ahmed M Basri, Zaki H Hakami, Tawfiq N Jurayb, Abdullah A Alqasem, Iman S Abumansour, Hind M Naffadi, Nasser A Elhawary, Hassan Rudayni, Mohammed Al-Zharani, Lina M Alneghery, Mohamed M I Ghoneim.

   BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide, with activating KRAS mutations representing a key oncogenic driver. These mutations profoundly reprogram cellular metabolism, especially glycolysis, thereby sustaining uncontrolled tumor proliferation. We identified ubiquitin-specific peptidase 15 (USP15) as a pivotal regulator in KRAS-driven metabolic remodeling and tumor progression. This study aims to elucidate the biological functions and molecular mechanisms of USP15 in KRASG12D/G13D-mutant NSCLC.
METHODS: Comprehensive bioinformatics analyses were performed to identify key metabolic genes significantly associated with NSCLC prognosis. The expression of USP15 was examined in KRAS-mutant NSCLC tissues and cell lines. Functional assays, including CCK-8, EdU incorporation, wound-healing, and subcutaneous xenograft tumor models, were employed to evaluate the oncogenic role of USP15 in vitro and in vivo. In addition, qPCR, Western blotting, ELISA, immunofluorescence, and Seahorse metabolic flux assays were integrated with transcriptomic and metabolomic profiling to comprehensively delineate the mechanisms by which USP15 regulates tumor metabolism and growth in KRASG12D/G13D-mutant NSCLC.
RESULTS: USP15 expression was elevated in KRAS-mutant NSCLC and was transcriptionally regulated by the MEK/ERK signaling pathway. Silencing USP15 significantly inhibited NSCLC cell proliferation, migration, and tumorigenicity, while inducing apoptosis and enhancing chemosensitivity. Multi-omics analyses revealed that USP15 exerts its oncogenic function primarily through modulation of the TGF-β/SMAD signaling axis. Mechanistically, USP15 stabilized SMAD4 by deubiquitination and promoted the phosphorylation of SMAD2/3, thereby sustaining TGF-β/SMAD pathway activation. Moreover, USP15 enhanced glycolytic flux, evidenced by increased extracellular acidification rates and upregulated glycolytic genes expression, ultimately facilitating metabolic adaptation and tumor progression in KRASG12D/G13D-mutant NSCLC.
CONCLUSION: USP15 acts as a critical mediator of oncogenic KRAS-driven metabolic reprogramming in NSCLC by promoting glycolysis via the TGF-β/SMAD signaling cascade. These findings uncover a previously unrecognized role of USP15 in linking metabolic regulation to tumorigenic signaling in KRAS-mutant NSCLC and suggest that targeting USP15 may represent a promising therapeutic strategy for this aggressive cancer subtype.

Keywords:  Glycolysis; KRAS(G12D)(/G13D); Non-small cell lung cancer; TGF-β/SMAD signaling; USP15

DOI:  https://doi.org/10.1016/j.lungcan.2025.108848
Cell Signal. 2025 Nov 27. pii: S0898-6568(25)00696-5. [Epub ahead of print] 112281

PPARG-FABP4 regulates PI3K/Akt pathway to promote lung cancer-associated macrophage endoplasmic reticulum stress-mediated CD36 expression and affects lung squamous cell carcinoma metastasis.

Zhen Li, Dongping Yu, Ning Wang, Hui Chen, Zhi Duan, Qiang Wu.

   BACKGROUND: Lung squamous cell carcinoma (LUSC) is a common subtype of primary lung cancer. Macrophage endoplasmic reticulum stress (ERS) is crucial in regulating lung cancer metastasis. Here, effects of Fatty acid binding protein 4 (FABP4) on macrophage ERS and lung cancer metastasis were evaluated.
METHODS: First, we used CancerSCEM single cell database to analyze interaction between tumor cells in LUSC and various immune cells in surrounding microenvironment. Database of The Cancer GenomeAtlas (TCGA) was utilized to analyze variations in mRNA expression and conduct survival analysis within lung cancer tissues. Then, 42 samples of LUSC tissue and corresponding adjacent normal tissues were obtained from patients. IHC staining evaluated FABP4 expression and co-localization with CD163. Lipid metabolic changes in macrophages were evaluated utilizing immunofluorescence and oil red O staining. Lung cancer cells (H520) were co-cultured with primary macrophages from lung cancer patients, and H520 cell proliferation, migration and invasion were detected. ChIP and dual luciferase reporter assays validated direct binding between peroxisome proliferator-activated receptor gamma (PPARG) and FABP4. Subcutaneous and metastatic tumor models were set up to confirm FABP4's impact on lung cancer progression in vivo.
RESULTS: FABP4 expression was upregulated in macrophages near cancer sites but declined in LUSC cancer epithelial cells. Silencing FABP4 in primary macrophages from lung cancer patients suppressed lipid metabolism in macrophages, reducing macrophage ERS and hindering lung cancer cell metastasis. PPARG enhanced FABP4 expression at the transcriptional level. PPARG-FABP4 controlled PI3K/Akt pathway, promoting ERS-induced CD36 expression in lung cancer-related macrophages, impacting lung cancer metastasis. Deleting macrophage FABP4 impaired both proliferation and metastasis of lung cancer in mice.
CONCLUSION: PPARG regulates FABP4 mRNA transcription, initiating macrophage ERS through PI3K/Akt-mediated lipid metabolism, thus modulating macrophage CD36 levels and influencing lung cancer metastasis.

Keywords:  CD36; FABP4; Lung cancer; Macrophage endoplasmic reticulum stress; PPARG

DOI:  https://doi.org/10.1016/j.cellsig.2025.112281
Int J Surg. 2025 Dec 03.

Integrative multi-omics identifies endoplasmic reticulum stress-related prognostic biomarkers and CD99-mediated cell-cell communication in lung adenocarcinoma.

Yi Rong, Liu-Rong Mao, Ya-Wei Liu, Wei-Dong Wang, Xia-Yu Fu, Han Yang, Jun-Ye Wang, Hong Yang, Hao-Xian Yang, Peng Lin, Kong-Jia Luo.

   BACKGROUND: Endoplasmic reticulum stress (ERS) plays a crucial role in tumor progression, yet its impact on lung adenocarcinoma (LUAD) heterogeneity and cell-cell communication (CCC) is not fully understood. Understanding how ERS shapes the tumor microenvironment (TME) is critical for the development of targeted therapies. This study investigated the impact of ERS on LUAD progression, immune evasion, and drug resistance by identifying ERS-related prognostic biomarkers and analyzing their effect on TME remodeling and CCC networks.
METHODS: Single-cell transcriptomics, bulk RNA sequencing, and spatial transcriptomics were integrated to identify ERS signatures and key genes in LUAD, investigating their effects on the TME, chemotherapy sensitivity, immune response and CCC. Consensus clustering based on the expression of ERS-related genes classified LUAD cases into two subtypes. A machine learning-based prognostic model was constructed. CCC networks were analyzed to identify critical mediators of ERS-driven interactions. Immunohistochemistry and qPCR were used to verify the correlation between the key genes and the occurrence and prognosis of LUAD.
RESULTS: Patients with LUAD were classified into two subtypes according to the expression of ERS-related genes. Subtype 1 was associated with significantly worse prognosis, differences in chemotherapy sensitivity, and altered immune checkpoint expression. Univariate Cox regression revealed 53 prognostic genes. A machine learning-based prognostic model demonstrated robust predictive ability and identified 29 ERS-related key genes. These genes significantly affected chemotherapy sensitivity and immune checkpoint expression. CD99-CD99 interactions were identified as key mediators of ERS-related CCC. The pan-cancer analysis revealed that key genes influence cell proliferation and anti-tumor immunity across various cancer types.
CONCLUSION: This study comprehensively analyzes ERS heterogeneity in LUAD, identifying novel key genes involved in the regulation of tumor proliferation, chemotherapy sensitivity, anti-tumor immunity, TME remodeling, and CCC networks. Furthermore, it highlights the critical role of CD99-mediated CCC in ERS, offering potential biomarkers and therapeutic targets for LUAD.

Keywords:  cell-cell communication; endoplasmic reticulum stress; lung adenocarcinoma; single-cell transcriptomics; spatial transcriptomics

DOI:  https://doi.org/10.1097/JS9.0000000000003888
Nat Commun. 2025 Dec 03.

Non-small cell lung cancer molecular subtypes and vulnerability to immunotherapy treatment combinations.

Tianshi Lu, Habib Hamidi, Mark A Socinski, Martin Reck, Federico Cappuzzo, Fabrice Barlesi, Robert M Jotte, Sören Müller, Aditi Qamra, Assaf Amitai, Xiangnan Guan, Eloisa Fuentes, Hartmut Koeppen, Jennifer M Giltnane, David S Shames, Marcus Ballinger, Meng Xiao He, Yulei Wang, Minu K Srivastava, Barzin Y Nabet.

The phase 3 IMpower150 trial in treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC) demonstrates significantly longer progression-free (PFS) and overall survival (OS) with first-line atezolizumab (anti-PD-L1)-bevacizumab (anti-VEGF)-carboplatin-paclitaxel (ABCP) than with bevacizumab-carboplatin-paclitaxel (BCP). We characterise four molecular NSCLC subtypes identified by unsupervised clustering of transcriptomes of 564 pre-treatment primary tumour samples from IMpower150 using non-negative matrix factorization (NMF1-4). Each subtype has distinct tumour PD-L1 expression levels, epithelial characteristics, immune composition, and treatment outcomes. Both NMF2 (enriched in tumour proliferation signal, macrophages, and monocytes) and NMF4 (enriched in B cells and T cells) have elevated tumour PD-L1 expression. Of these two, only NMF4 demonstrates PFS and OS benefits with ABCP versus either BCP or atezolizumab-carboplatin-paclitaxel (ACP). Patients with NMF1 (enriched in basal and squamous-like cells) have improved outcomes on ABCP compared with ACP or BCP; those with NMF3 (enriched in adenocarcinoma signatures) show similar outcomes among treatments. These insights could help inform individualised first-line treatment for metastatic NSCLC.

DOI: https://doi.org/10.1038/s41467-025-66803-8
Cancer Biol Ther. 2025 Dec 31. 26(1): 2590881

Toll-like receptor 4 inhibition sensitizes non-small cell lung cancer to radiotherapy.

Ryma Haroun, Cleopatra Rutihinda, Aissatou Hadja Diallo, Juan Pablo Ordonez, Sahar Nassri, Aliya Shams, Maria Fernanda Meza Pacheco, Nour Elhouda Saidi, Lea Bouchard, Guy-Anne Turgeon, Denis Gris, Lee-Hwa Tai, Ayman J Oweida.

  Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although radiotherapy (RT) is used to treat over half of NSCLC patients, about 30% have inherent or acquired radioresistance leading to treatment failure. There's a clinically unmet need to investigate mechanisms of radioresistance that can be targeted in combination with RT. Among these, HMGB1 has been shown to play a key role in tumor progression. Our research investigates TLR4, a receptor for HMGB1, highly expressed in NSCLC tissues, as a mediator of radioresistance.
METHODS: The TLR4 inhibitor, TAK242, was tested in NSCLC cell lines (murine: LLCI, KLN205; human: H1975, SW900). Cells were irradiated at 2 and 10 Gy. In vivo, KLN205 cells were implanted in DBA/2 mice and tumors were irradiated at 10Gy. Gene and protein expression of TLR4 and MyD88 were assessed in vitro and in vivo. HMGB1 secretion was quantified after RT. Clonogenic assays were performed to evaluate the effect of TAK242 on radiosensitivity in vitro. The combination of TAK242 and RT was investigated in vivo in mice bearing KLN205 tumors.
RESULTS: TAK242 significantly decreased NSCLC cell proliferation and migration. Radiation at 2 and 10 Gy increased TLR4 gene expression in vitro and in vivo in a dose-dependent manner. In vitro, TLR4 and HMGB1 protein expression was upregulated following radiation. TAK242 in combination with radiation enhanced radiosensitivity in vitro. TAK242 decreased the percentage of cells in the G1 phase, coupled with an increase in late S and G2/M, suggesting radiosensitization via cell cycle modulation. In vivo, the combination of RT and TAK242 significantly reduced growth of KLN205 tumors.
CONCLUSION: These findings show that TLR4 inhibition enhances RT sensitivity in NSCLC.

Keywords:  HMGB1; Radiotherapy; immunotherapy; non-small cell lung cancer; radioresistance; toll-like receptor 4

DOI:  https://doi.org/10.1080/15384047.2025.2590881