Single-nucleus multi-omics profiling reveals cell state transitions and epigenetic programs in lung adenocarcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE304587 | GEO | 2026/06/03
REPOSITORIES: GEO
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Project description:Single-nucleus multi-omics profiling reveals cell state transitions and epigenetic programs in lung adenocarcinoma
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Project description:Xuanwei lung cancer (XWLC) is well-known for its high incidence and mortality, especially among non-smoking female patients. However, the molecular mechanism is still unclear. Here, we performed a comprehensive transcriptomic, proteomic, and phosphoproteomic characterization of tumors and matched normal adjacent tissues from three non-smoking female XWLC patients with lung adenocarcinoma (LUAD). Integrated transcriptome and proteome analysis revealed dysregulated molecules and pathways in tumors and identified enhanced metabolic-disease coupling. Non-coding RNAs were widely involved in post-transcriptional regulatory mechanisms to coordinate the progress of LUAD, and also partially explained the molecular differences between RNA and protein expression patterns. Phosphoproteome provided evidence support for new phosphate sites, reporting the potential roles of core kinase family members and key kinase pathways involved in metabolism, immunity, as well as homeostasis. In addition, by comparing with the previous large-scale LUAD researches, we emphasized the higher degree of oxidative phosphorylation (OXPHOS) in Xuanwei LUAD, and pointed that VIPR1 deficiency aggravated immune dysfunction. Overall, our integrated multi-omics analysis provided a powerful resource for a systematic understanding of the molecular structure of XWLC and proposed therapeutic opportunities based on redox metabolism and immune cell infiltration.
2024-01-03 | GSE165298 | GEO
Project description:We conducted a proteomic analysis of LUAD patients with KRAS G12 mutations, and explore the interactome of KRAS G12 proteins. In conclusion, the findings of this study provide a deep understanding of the molecular mechanism of KRAS G12 mutation-driven LUAD.
2026-06-08 | PXD058891 | Pride
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Project description:Non-small cell lung cancer (NSCLC) comprises the majority (~85%) of all lung tumors, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being the most frequently diagnosed histological subtypes. Currently, multi-modal omics profiles had been carried out in NSCLC, but no studies reported yet a systems biology approach to provide a complete picture of molecular perturbations specifically for LUAD and LUSC.
2022-05-04 | GSE159857 | GEO
Project description:The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing of samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could be used to categorize tumors into molecular subtypes within pathology-defined types of lesions. These subtypes were linked with the advanced radiology-defined type of lesions and corresponded to immune cell infiltration throughout the early progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.
2024-11-01 | GSE277206 | GEO
Project description:Mammalian SWI/SNF complexes are ATP-dependent chromatin remodelers composed of varying combinations of subunits that, together, fine-tune transcriptional regulation and genome integrity. SWI/SNF complex subunits have been identified as major targets of mutations in several tumor types suggesting a relevant role in tumorigenesis. However, there is a lack of comprehensive studies of the whole SWI/SNF complex in lung adenocarcinoma (LUAD). Here, we combined genomic, transcriptomic, and proteomic approaches to identify which SWI/SNF subunits are present in lung cells, as well as their mutational status, mRNA levels, and protein levels in LUAD. For these purposes, we combined data from LUAD primary tumors, normal lung and LUAD cell lines, and external LUAD data from The Cancer Genome Atlas. Importantly, we found that mutations in the SWI/SNF complex in LUAD not only present a high incidence but we also observed that only the mutational status of the SWI/SNF complex and not the mutations in any of the top ten LUAD driver genes is associated with poorer overall survival in LUAD patients. Furthermore, we showed that the expression of the SWI/SNF complex in LUAD suffers an overall repression that cannot be explained exclusively by genetic alterations. Based on our findings, we propose that SWI/SNF-mutant LUAD tumors should be considered as a distinct subgroup with practical applications in the prognosis and follow-up of LUAD patients.
2022-04-01 | PXD017397 | Pride
Project description:Dysregulated kinase activity drives oncogenic signalling, perturbs cellular homeostasis, and promotes tumour progression. Despite major success in targeting kinases therapeutically, the downstream consequences of kinase inhibition and the mechanisms underlying drug resistance remain incompletely understood. One of the most frequent oncogenic kinase mutations, BRAFV600E, constitutively activates the MAPK pathway and represents a major therapeutic target in melanoma and other cancers. However, the functional relevance of most phosphorylation events downstream of BRAF signalling is unknown, limiting mechanistic interpretation and rational therapeutic design. Here, we established a global, multi-omic model of BRAF inhibition response in BRAFV600E-mutant melanoma cells by integrating time-resolved phosphoproteomics, biophysical PTM-proteomics, transcriptomics, and thermal proteome profiling. Our ultradeep phosphoproteomic analysis revealed widespread phosphorylation changes upon Dabrafenib treatment, while biophysical phosphoproteomics uncovered phosphorylation events associated with altered solubility and subcellular localisation, indicative of biomolecular condensation and nuclear reorganisation. Integration of these modalities into a network-based mechanistic model enabled the prioritisation of functionally relevant phosphorylation sites and kinases. Experimental validation confirmed CDK9, CLK3, and TNIK as key regulators of BRAFV600E signalling and as candidate targets for combinatorial inhibition strategies capable of re-sensitising resistant melanoma cells in a synthetic lethal manner. The transcription factor ETV3 emerged from the network as a previously unrecognised effector of oncogenic BRAF signalling. Using phosphosite-specific biophysical data, imaging, and FRAP experiments, we demonstrated that ETV3 phosphorylation controls its DNA-binding kinetics. Functional assays combining ETV3 knockdown, metabolomics, and drug screening revealed that ETV3 modulates transcriptional and metabolic responses to BRAF inhibition, linking oncogenic signalling to metabolic rewiring. Together, this study provides a comprehensive systems-level framework that connects phosphorylation dynamics to protein function and cellular phenotype, highlights ETV3 as a novel signalling node, and illustrates how multi-omic, site-resolved network models can reveal actionable mechanisms of kinase-driven oncogenesis.
2026-01-01 | E-MTAB-16292 | biostudies-arrayexpress
Project description:Lineage plasticity is critical for tumor progression and therapy resistance, but the molecular mechanisms underlying cell identity shifts in cancer remain poorly understood. In lung adenocarcinoma (LUAD), the loss of pulmonary lineage fidelity and acquisition of alternate identity programs converge on hybrid-identity (hybrid-ID) states which are postulated to be key intermediates in LUAD evolution and are characterized by the co-activation of developmentally incompatible identity programs within individual cells. Here, we uncover a previously unrecognized role for the gastrointestinal transcriptional regulator HNF4α in driving tumor growth and hybrid-ID states in LUAD. In LUAD cells expressing the lung lineage specifier NKX2-1, HNF4α induces a GI/liver-like state by directly binding and activating its canonical targets. HNF4α also disrupts NKX2-1 genomic localization and dampens pulmonary identity within hybrid-ID LUAD. We show that this hybrid-ID state is maintained by sustained by RAS/MEK signaling. Inhibition of the RAS/MEK signaling cascade augments NKX2-1 chromatin binding at pulmonary-specific genes and induces drug resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4α depletion sensitizes LUAD cells to KRASG12D inhibition. Collectively, our data show that co-expression of opposing lineage specifiers is a novel mechanism of identity dysregulation in LUAD that influences both tumor progression and response to targeted therapy.
2025-06-13 | GSE281964 | GEO
Project description:Lineage plasticity is critical for tumor progression and therapy resistance, but the molecular mechanisms underlying cell identity shifts in cancer remain poorly understood. In lung adenocarcinoma (LUAD), the loss of pulmonary lineage fidelity and acquisition of alternate identity programs converge on hybrid-identity (hybrid-ID) states which are postulated to be key intermediates in LUAD evolution and are characterized by the co-activation of developmentally incompatible identity programs within individual cells. Here, we uncover a previously unrecognized role for the gastrointestinal transcriptional regulator HNF4α in driving tumor growth and hybrid-ID states in LUAD. In LUAD cells expressing the lung lineage specifier NKX2-1, HNF4α induces a GI/liver-like state by directly binding and activating its canonical targets. HNF4α also disrupts NKX2-1 genomic localization and dampens pulmonary identity within hybrid-ID LUAD. We show that this hybrid-ID state is maintained by sustained by RAS/MEK signaling. Inhibition of the RAS/MEK signaling cascade augments NKX2-1 chromatin binding at pulmonary-specific genes and induces drug resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4α depletion sensitizes LUAD cells to KRASG12D inhibition. Collectively, our data show that co-expression of opposing lineage specifiers is a novel mechanism of identity dysregulation in LUAD that influences both tumor progression and response to targeted therapy.
2025-06-13 | GSE281961 | GEO