IGF2BP3-TRIM37-P53 axis promotes tumor progression in LUAD.

From palmitoylation to cholesterol metabolism: The hidden mechanism of lung tumorigenesis.

circHIF1A/miR-486-5p/GRHL2 axis induces macrophage M2 polarization to accelerate lung adenocarcinoma progression.

Cigarette smoke-induced endothelial senescence-like phenotype promotes lung adenocarcinoma metastasis via the BMP4-Smad1/5/9-ID1 axis.

Accurate diagnosis of lung adenocarcinoma (LUAD), particularly in small biopsy specimens, can be challenging due to limited tissue availability and the presence of histological mimickers. Claudin-18 (Cldn18), a tight junction protein with a lung-specific isoform (Cldn18.1), is normally expressed in alveolar epithelium and is implicated in maintaining alveolar integrity. Loss of Cldn18 has been linked to LUAD development through dysregulated YAP signalling. This study evaluated Cldn18 expression across lung cancer subtypes, with particular focus on LUAD. Cldn18 immunohistochemical expression was retrospectively assessed in 391 lung resection specimens and 53 small biopsy samples. Normal alveoli and reactive pneumocytes consistently expressed Cldn18, whereas LUADs, especially non-mucinous LUADs (NM-LUADs), typically showed marked loss. Complete absence of Cldn18 was observed in 83% of NM-LUAD resections and 84.8% of NM-LUAD biopsies. ROC analysis demonstrated excellent diagnostic accuracy (AUC 0.992), with sensitivity of 98.4% and specificity of 100%. Lepidic NM-LUAD components, a frequent diagnostic pitfall especially in small specimens, showed low expression in most cases (>50% of tumour cells in 24/26). Similarly, 6/7 atypical adenomatous hyperplasia (AAH) cases exhibited low expression, while all reactive pneumocyte proliferations retained staining. By contrast, mucinous LUADs (M-LUADs) preserved Cldn18 expression in 35/54 cases, providing a clear distinction from NM-LUADs with mucin production. Cldn18 loss is a promising diagnostic biomarker for NM-LUAD. Complete loss of Cldn18 expression could serve as an ancillary tool for distinguishing malignant lesions from NM-LUAD mimickers and for differentiating NM-LUADs with mucin production from true M-LUADs, particularly in small or challenging biopsies.

Recruitment of tumor-associated macrophages via the CCL4-CCR5 axis promotes immune escape through PD-1 signaling in lung adenocarcinoma.

CCT7 is a chaperonin containing tailless complex polypeptide 1 subunit. The study focused on investigating its prognostic significance for lung adenocarcinoma (LUAD). CCT7 expression in LUAD and matched non-carcinoma lung samples was examined via TCGA database. Besides, we utilized the GEO database and RT-qPCR for validating differential CCT7 expression. The relation with clinical factors and its functions in diagnosis and prognosis prediction were determined. GO, KEGG, along with GSEA were conducted for exploring CCT7's functions. We also performed CIBERSORT, ssGSEA, and ESTIMATE for examining the LUAD immune microenvironment. By analyzing tumor mutational burden (TMB) and immune checkpoints, the relationship between CCT7 and immunotherapy was explored. CCT7 expression significantly increased within LUAD relative to matched non-carcinoma lung samples. As revealed by GO, KEGG, as well as GSEA results, CCT7 was mostly related to cell movement and regulation of multiple biological processes. Furthermore, CCT7 expression varied significantly among different immune cells, and those having increased CCT7 expression showed greater TMB. An increase in CCT7 expression carries significant implications for diagnosing and predicting LUAD prognosis.

Epidemiological studies have indicated a strong link between metabolic disease and an elevated risk of cancer. However, it has not been directly replicated in animal models, nor has its specific underlying mechanism been clarified. From our previous research, liver-specific SIRT1 knockout (LKO) mice developed hyperglycemia within two months and developed fatty liver with whole-body insulin resistance around nine months of age. When the mice's age extended to one year, they presented surprisingly higher lung tumor vulnerabilities in contrast to wild type as determined by macroscopic observation and histological examination. Interestingly, all lung tumors in these mice were classified as lung adenocarcinomas. Microarray analysis revealed elevated levels of MDM2, an oncoprotein, leading to the downregulation of its target genes such as p21 and GADD45. In vitro, the disruption of MDM2 leads to impaired cell cycle checkpoints and increased cell proliferation, which is accompanied by genomic instability, eventually causing full transformation in normal lung epithelia. In addition, the heat shock factor 1 (HSF1) transcription factor was found to regulate MDM2 directly and would decrease in the nucleus under high glucose conditions. Knockdown of HSF1 in the bronchial epithelial cell line (NL20) can increase MDM2 expression and cell proliferation. Human lung adenocarcinomas also displayed elevated MDM2 levels, with a correlation between MDM2 expression and lung cancer survival rates. Collectively, our findings suggest that liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through the HSF1-MDM2 pathway. Hyperglycemia may represent an underexplored cause of lung adenocarcinomas through impairment of cell cycle checkpoints, providing valuable insights for lung cancer prevention and future precision medicine.

Single-cell and spatial transcriptomic profiling of POU5F1 in Lung Adenocarcinoma: Dynamics, spatial niche, and prognosis via multi-algorithm ML.

Antibody-drug conjugates (ADC) targeting trophoblast cell surface antigen 2 (TROP-2) and cMET are entering clinical trials in non-small cell lung cancer (NSCLC). Their translation depends on reliable biomarker assessment, a task still dominated by subjective visual scoring and inconsistent reproducibility. We built a modular Artificial Intelligence (AI) pipeline that detects cells, classifies carcinoma cells, and quantifies membranous and cytoplasmic expression. A membranous scorer trained on TROP-2 was applied zero-shot to cMET, human epidermal growth factor receptor 2 (HER2), and PD-L1. For TROP-2, cMET, and HER2, expression was quantified using the H-score, defined as (1× % weakly positive cells) + (2× % moderately positive cells) + (3× % strongly positive cells), with negative cells excluded (range, 0-300), and categorized as negative (0-50), weakly positive (50-100), moderately positive (100-200), or strongly positive (200-300). PD-L1 expression was assessed using both the H-score and the tumor proportion score (TPS), defined as the percentage of viable tumor cells showing membranous PD-L1 staining relative to all viable tumor cells, multiplied by 100. The analysis covered 1,142 resected NSCLCs, integrating expression maps with clinicopathologic, molecular, and tumor microenvironment (TME) features. The AI scorer recapitulated pathologist annotations with near-perfect correlation [Pearsons's correlation (r) = 0.98-0.99, Spearman's rho (ρ) = 97-98, Kendall's tau (τ) = 0.88-0.89, Lin's concordance correlation coefficient (CCC) = 0.97-0.98] for TROP-2 and generalized to other markers [cMET r = 0.99, ρ = 0.96, τ = 0.91, CCC = 0.96; HER2 r = 0.93, ρ = 0.72, τ = 0.60, CCC = 0.92; and PD-L1 (TPS) r = 0.85, ρ = 0.84, τ = 0.68, CCC = 0.82/(H-score) r = 0.87, ρ = 0.86, τ = 0.70, CCC = 0.85]. Its agreement with six pathologists matched interobserver variability (0.86-0.96). Expression maps revealed contrasting spatial and cellular patterns: TROP-2 dominated lung squamous cell carcinoma [LUSC; mean H-Scores 141.3/103.2 vs. 74.5/45.7 in lung adenocarcinoma (LUAD) for membrane/cytoplasm] and marked immune-deserted tumors. cMET prevailed in LUAD (mean 50.4 vs. 20.6 in LUSC), colocalized with fibroblast-rich, immune-active TME, and KRAS mutations. Foundation model-based scoring produces expert-level, scalable biomarker quantification. The resulting TME phenotypes-TROP-2-high immune-deserted versus cMET-high, immune-active-reveal therapeutic implications for combining ADCs with immunotherapies or kinase inhibitors.

267 Background: Lung cancer, especially non-small cell lung cancer (NSCLC), exhibits significant molecular heterogeneity that influences treatment response and clinical outcomes. This study aims to explore genetic variations and actionable alterations in Indian NSCLC patients to enhance precision medicine approaches. Methods: FFPE tumor tissue samples from 227 Indian lung cancer patients were analyzed using the 1Cell.Ai OncoTarget panel, a targeted NGS assay covering 126 genes associated with multi-cancer mutations, driver fusions, and microsatellite instability. Genomic DNA extraction, library preparation, and sequencing were performed on the Illumina NextSeq platform. Variant calling and clinical interpretation were conducted using the AI-driven iCARE software to identify somatic mutations, gene fusions, copy number variations (CNVs), and other genomic alterations. Therapeutic recommendations followed ACMG, AMP, ASCO, and CAP guidelines. Results: Comprehensive molecular profiling revealed frequent alterations in TP53 (116 cases; 51.1%), EGFR (98 cases; 43.2%), PIK3CA (20 cases; 8.8%), KRAS (15 cases; 6.6%), APC (12 cases; 5.3%), and ALK (11 cases; 4.8%). A clinically significant TP53–EGFR dual-mutation signature was observed in lung adenocarcinoma, with a high co-occurrence rate of approximately 59% (65 cases), defining a distinct molecular subtype characterized by differential responses to EGFR tyrosine kinase inhibitors, an increased propensity for accelerated therapeutic resistance, and a higher risk of aggressive disease progression. Additionally, KRAS co-mutation with TP53 was identified in 10 cases (66.67%), a pattern associated with adverse clinical outcomes, poorer prognosis, and reduced responsiveness to immunotherapy. Importantly, the detection of the KRAS G12C subtype highlights eligibility for targeted therapies such as sotorasib and adagrasib. Among evaluable cases for therapeutic recommendations (n = 160), EGFR mutations were present in 41.66% (67/160) and demonstrated favourable responses to EGFR-directed TKIs, although TP53 co-mutations contributed to resistance in a subset, while ALK fusions (15.63%; 25/160) showed marked sensitivity to ALK inhibitor–based targeted therapies. Conclusions: This study demonstrates the diverse genomic landscape of Indian NSCLC patients, highlighting TP53 and EGFR as key drivers. Notably, 160 of 227 patients (70.48%) received therapy recommendations based on genomic alterations, underscoring the translational value of targeted NGS panels in advancing precision medicine beyond conventional chemotherapy.

Finite element modelling for elucidating surface topography influence on cell-substrate interaction on fatty acid-modified PCL substrate.

The potential treatment option of targeting protein arginine methyltransferase 5 (PRMT5) has been explored, but further investigation is required to assess the efficacy of combination therapy in non-small cell lung cancer (NSCLC). In this study, bioinformatics and online databases were utilized to select the combined therapeutic targets. The potential kinases associated with PRMT5-related genes in NSCLC were analyzed using The Cancer Genome Atlas (TCGA) database and X2K Appyter (Expression2Kinases) database. In vitro evaluations were conducted to assess the synergistic effects between PRMT5 and cyclin-dependent kinase 1 (CDK1) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cell lines. In our study, CDK1 was primarily the kinase associated with PRMT5-related genes in NSCLC. We observed a significant upregulation of PRMT5 and CDK1 expression in NSCLC tissues. Methylthioadenosine phosphorylase (MTAP)-null NSCLC cell lines demonstrated sensitivity to monotherapy with PRMT5i. A considerable synergistic effect was observed in MTAP-null cells when combining PRMT5i with CDK1i, resulting in the inhibition of cell growth and migration. Our research provides evidence supporting the synergistic anti-tumor effects of targeting PRMT5 and CDK1 in MTAP-deficient NSCLC.

Cells use plasticity programs to change lineages, which aids in tissue regeneration and remodeling but also allows aberrant cells to become cancerous and escape therapy. For example, tumor cells in invasive mucinous adenocarcinoma (IMA) emerge from lung epithelial cells by a plasticity program that reprograms them into gastric epithelium-like cells. In this issue of the JCI, Dadzie et al. show that hepatocyte nuclear factor 4 α (HNF4α) promotes gastric identity in lung epithelial cells via a mechanism involving restriction of FOXA1 and FOXA2 transcription factors to gastric gene enhancer loci. HNF4α also promotes resistance to KRAS inhibition by increasing nuclear factor erythroid 2-related factor 2 (NRF2) activity. These findings may advance therapeutic avenues in IMA.

Herein, we report four new cationic ruthenium(II)-(p-cymene) racemic complexes (C1-C4) containing N,S-coordinated pyrazoline ligands. The contemplated organoruthenium compounds from dimeric Ru(II)-(η6p-cymene) chlorido moieties and pyrazoline-based ligands were synthesized and characterized using standard analytical, spectral and ESI-HRMS data. The pseudo-octahedral geometry, neutral bidentate N and S chelation of pyrazoline thiosemicarbazones, and cationic nature of all four complexes were confirmed through single-crystal X-ray diffraction (SC-XRD) study. The geometry of individual enantiomers of the respective enantiomeric pairs was optimized using density functional theory. Furthermore, frequency calculations, single-point calculations, frontier molecular orbital analysis and TD-DFT were also carried out. Biomolecular interactions of the complexes were investigated using UV-visible and fluorescence spectroscopy techniques with calf-thymus DNA (CT-DNA) and bovine serum albumin (BSA). Anticancer activity of the racemic complexes C1-C4 against human colorectal adenocarcinoma (HT-29) and human lung cancer (A549) cell lines assessed using MTT assay indicated the IC50 concentrations ranging from 15.39 to 21.86 µM and 17.29 to 24.29 µM for HT-29 and A549 cells, respectively, and the values are comparable to that of the positive control (cisplatin) and also the same assay was performed on human epithelial kidney cells (HEK-293) to determine the selectivity index of the complexes. As these four complexes possess similar molecular structures, based on the better selectivity index and promising in vitro performance, complex C2 was selected for more detailed anticancer assays. DAPI, DCFDA, and JC-I cellular staining assays, along with flow cytometry, were performed on C2-treated A549 cells. The complex C2 induced apoptosis through DNA damage, ROS generation, and mitochondrial depolarization. Molecular docking studies on the DFT-optimized R and S conformers of the complexes were undertaken towards a spectrum of cancer-related protein targets to validate their binding interactions. The complexes demonstrated favorable binding interactions with B-DNA, BSA, cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2), with high binding affinity values of -8.12, -6.6, -6.25 and -7.53 kcal mol-1, respectively. Simultaneously, binding interactions of the individual enantiomers (R and S) of the respective pairs of each complex towards the target proteins were also examined, but they did not vary greatly among the complexes.

Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary to gastric switch marked by aberrant activation of hepatocyte nuclear factor 4 alpha (HNF4α), a master regulator of gastrointestinal/hepatic differentiation. We show that HNF4α promoted IMA growth and activated a gastric pit cell-like program. Loss of HNF4α enabled forkhead box A1 and A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, nongastric identities in IMA. HNF4α also established a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhanced response to KRASG12D inhibition. Mechanistically, HNF4α blocked cell-cycle exit in drug-tolerant persister cells and promoted activity of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 activation partially rescued the effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhanced sensitivity to KRASG12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRASG12D inhibition in IMA.

The establishment of monoclonal, stably transduced cell lines is a critical step in functional genomics and drug discovery. However, conventional methods are often time-consuming, labor-intensive, and prone to compromising cell viability. Here, we present a microfluidic single-cell sorting system based on laser-induced jetting (LIJet) that significantly improves the efficiency and quality of stable cell line generation. This system integrates a light-responsive substrate with metal coating and a PDMS microfluidic chip featuring an array of microwells, enabling single-cell capture, identification, and non-contact precision release. A 532nm nanosecond pulsed laser is used to generate localized microjets, which accurately eject target cells from the microwells. In addition to achieving a 100% sorting success rate and maintaining over 95.3% post-sorting cell viability, the system supports long-term on-chip culture and viral transduction with full real-time monitoring. We demonstrated the platform's functionality by performing on-chip ZsGreen lentiviral transduction of human lung adenocarcinoma PC9 cells, followed by fluorescence-based single-cell selection, ultimately establishing monoclonal cell lines with stable transgene expression. This platform offers notable advantages in low-damage manipulation, dynamic monitoring, and functional perturbation, providing a robust and efficient solution for the construction of stably transduced cell lines, gene function screening, and phenotypic analysis across a variety of biomedical applications.

The role of germline mutations in non-small cell lung cancer: A systematic review of emerging genetic drivers and clinical implications.

CYP2A13 upregulation contributes to lung tumorigenesis upon NNK exposure.

Single Lung Transplant Following Contralateral Pneumonectomy for Treatment of Recurrent Lung Adenocarcinoma