RNA-sequence data of clinically never-metastatic primary small cell lung cancer cases and small cell lung cancer metastasis cases, FOXA2 knock-down and overexpression in cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE281525 | GEO | 2025/04/13
REPOSITORIES: GEO
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Project description:Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compared gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identified FOXA2 as a transcription factor strongly associated with SCLC metastasis. Subsequent analyses in experimental models demonstrated that FOXA2 induces a fetal neuroendocrine gene expression program and promotes multi-site metastasis. Moreover, we identified ASCL1, a transcription factor known for its initiating role in SCLC tumorigenesis, as a direct binder of the FOXA2 promoter and regulator of FOXA2 expression. Taken together, these data define the ASCL1-FOXA2 axis as a critical driver of multiorgan SCLC metastasis.
2025-04-13 | GSE281740 | GEO
Project description:Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compared gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identified FOXA2 as a transcription factor strongly associated with SCLC metastasis. To clarify the contribution of ASCL1 with the interaction with FOXA2, we performed ATAC-seq on clinical FFPE samples, and PDX samples to analyze the chromatin accessibility in FOXA2+ and FOXA2- state. Furthermore, we confirmed the binding of ASCL1 by ChiP-sequence.
2025-04-13 | GSE281524 | GEO
Project description:Small cell lung cancer (SCLC) is known for its high metastatic potential, with most patients demonstrating clinically evident metastases in multiple organs at diagnosis. The factors contributing to this exceptional metastatic capacity have not been defined. To bridge this gap, we compared gene expression in SCLC patient samples who never experienced metastasis or relapse throughout their clinical course, versus primary SCLC patient samples from more typical patients who had metastatic disease at diagnosis. This analysis identified FOXA2 as a transcription factor strongly associated with SCLC metastasis. To clarify the contribution of ASCL1 with the interaction with FOXA2, we performed ATAC-seq on clinical FFPE samples, and PDX samples to analyze the chromatin accessibility in FOXA2+ and FOXA2- state. Furthermore, we confirmed the binding of ASCL1 by ChiP-sequence.
2025-04-13 | GSE281523 | GEO
Project description:Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and it is positively associated with SCLC progression. ERRγ functions as an essential activator of ECM remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilaments production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppress tumor growth and metastasis and restore resistant SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.
2024-05-15 | GSE259272 | GEO
Project description:Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and it is positively associated with SCLC progression. ERRγ functions as an essential activator of ECM remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilaments production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppress tumor growth and metastasis and restore resistant SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.
2024-05-15 | GSE259271 | GEO
Project description:Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. Most patients are diagnosed at an extensive stage. However, the molecular mechanisms driving SCLC invasion and metastasis remain largely elusive. We used an autochthonous SCLC mouse model and matched primary and metastatic SCLC patient samples to investigate the molecular characteristics of tumor metastasis. We demonstrate that tumor cell invasion and liver metastasis in SCLC are triggered by an Angiopoietin-2/Integrin beta-1-dependent pathway in tumor cells, mediated by focal adhesion kinase-Src kinase signaling. Strikingly, CRISPR-Cas9 knock out of Integrin beta-1 or blocking Integrin beta-1 signaling by an anti-Angiopoietin-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched primary and metastatic SCLC patient samples confirmed a strong increase of Integrin beta-1 in liver metastasis in comparison to the primary tumor. We further show that Angiopoietin-2 blockade combined with anti-VEGFR and PD-1-targeted treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of Angiopoietin-2/Integrin beta-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a new effective treatment strategy for patients with SCLC.
2024-03-28 | GSE262409 | GEO
Project description:Objectives: Small cell lung cancer (SCLC) is characterized by poor prognosis and challenging diagnosis. Screening in high-risk smokers results in a reduction in lung cancer mortality, however, screening efforts are primarily focused on non-small cell lung cancer (NSCLC). SCLC diagnosis and surveillance remain significant challenges. The aberrant expression of circulating microRNAs (miRNAs/miRs) is reported in many tumors and can provide insights into the pathogenesis of tumor development and progression. Here, we conducted a comprehensive assessment of circulating miRNAs in SCLC with a goal of developing a miRNA-based biomarker classifier to assist in SCLC diagnoses. Materials and Methods: We profiled deregulated circulating cell-free miRNA in the plasma of SCLC patients. We tested selected miRs on a training cohort and created a classifier by integrating miRNA expression and patient clinical data. Finally, we applied the classifier on a validation dataset. Results: We determined that miR-375-3p can discriminate between SCLC and NSCLC patients, and between SCLC and Squamous Cell Carcinoma patients. Moreover, we found that a model comprising miR-375-3p, miR-320b, and miR-144-3p can be integrated with race and age to distinguish metastatic SCLC from a control group. Conclusion: This study proposes a miRNA-based biomarker classifier for SCLC that considers clinical demographics with specific cut offs to inform SCLC diagnosis.
2023-10-31 | GSE240758 | GEO
Project description:Objectives: Small cell lung cancer (SCLC) is characterized by poor prognosis and challenging diagnosis. Screening in high-risk smokers results in a reduction in lung cancer mortality, however, screening efforts are primarily focused on non-small cell lung cancer (NSCLC). SCLC diagnosis and surveillance remain significant challenges. The aberrant expression of circulating microRNAs (miRNAs/miRs) is reported in many tumors and can provide insights into the pathogenesis of tumor development and progression. Here, we conducted a comprehensive assessment of circulating miRNAs in SCLC with a goal of developing a miRNA-based biomarker classifier to assist in SCLC diagnoses. Materials and Methods: We profiled deregulated circulating cell-free miRNA in the plasma of SCLC patients. We tested selected miRs on a training cohort and created a classifier by integrating miRNA expression and patient clinical data. Finally, we applied the classifier on a validation dataset. Results: We determined that miR-375-3p can discriminate between SCLC and NSCLC patients, and between SCLC and Squamous Cell Carcinoma patients. Moreover, we found that a model comprising miR-375-3p, miR-320b, and miR-144-3p can be integrated with race and age to distinguish metastatic SCLC from a control group. Conclusion: This study proposes a miRNA-based biomarker classifier for SCLC that considers clinical demographics with specific cut offs to inform SCLC diagnosis.
2023-10-31 | GSE240757 | GEO
Project description:Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multi-omics analyses. We found that loss of KMT2C, an H3K4 methyltransferase frequently mutated in extensive stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C deficient SCLC through repressing metastasis promoting MEIS/HOX genes. Further, S-(5’-Adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a new epigenetic therapeutic vulnerability.
2022-02-23 | GSE161570 | GEO
Project description:Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine cancer that is typically metastatic upon diagnosis, and has low overall survival. Despite being highly sensitive to first-line chemotherapy or radiotherapy, most patients with SCLC experience relapse and succumb from systemic metastasis. Here we report that inactivation of ABL tyrosine kinases markedly impaired outgrowth of metastatic SCLC tumors in mouse models, resulting in prolonged animal survival. Mechanistically, ABL inactivation in SCLC resulted in increased accumulation of transcription-replication conflicts, compromised replication fork progression, impaired expression and function of proteins implicated in transcription-coupled homologous recombination, and increased DNA damage. Because ABL inactivation increased DNA damage, we evaluated whether blocking the activity DNA damage-repair pathways in the presence of ABL inhibitors might synergize to promote SCLC cell death. We found that co-inactivation of ABL kinase and Ataxia telangiectasia and Rad3-related (ATR), the primary responder of replication stress, synergistically inhibited SCLC cell growth in vitro, and impaired metastatic dissemination and outgrowth compared to single agent treated mice. Thus, combined inactivation of ABL kinase and DNA damage-repair pathways might be exploited to block dissemination and outgrowth of SCLC metastases
2025-02-13 | GSE289452 | GEO