The role of S100A9 in brain metastesis in EGFR-mutant lung cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788130 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17205200_1.fastq.gz | Fastqsanger.gz | |||
| SRR17205200_2.fastq.gz | Fastqsanger.gz | |||
| SRR17205201_1.fastq.gz | Fastqsanger.gz | |||
| SRR17205201_2.fastq.gz | Fastqsanger.gz | |||
| SRR17205184_1.fastq.gz | Fastqsanger.gz |
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Project description:Metastatic relapse from treatment failure has been a formidable challenge to finding a cure for EGFR-mutant lung cancer. Metastasis to the brain is a severe complication for 45% of patients with EGFR-mutant lung cancer that drastically reduces their quality of life and survival. Here, we demonstrate that genetic inhibition of S100A9, ALDH1A1, RAR, or pharmacological inhibition of the RA pathway using pan-RAR inhibitors significantly reduces brain relapse from osimertinib-refractory cancer cells. Our study has therefore revealed a novel S100A9-ALDH1A1-RA signaling axis in the EGFR-mutant lung cancer cells that drives osimertinib-refractory metastatic brain relapse and identified a potential vulnerability in lung cancer cells that can be therapeutically targeted to prolong progression-free survival in EGFR-mutant lung cancer patients.
2023-12-20 | GSE190704 | GEO
Project description:The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has significantly prolonged progression-free survival (PFS) in patients with EGFR-mutant lung cancer, including those with brain metastases. However, despite striking initial responses, osimertinib-treated patients eventually develop lethal metastatic relapse, often to the brain. Although osimertinib-refractory brain relapse is a major clinical challenge, its underlying mechanisms remain poorly understood. Using metastatic models of EGFR-mutant lung cancer, we show that cancer cells expressing high intracellular S100A9 escape osimertinib and initiate brain relapses. Mechanistically, S100A9 upregulates ALDH1A1 expression and activates the retinoic acid (RA) signaling pathway in osimertinib-refractory cancer cells. We demonstrate that the genetic repression of S100A9, ALDH1A1, or RA receptors (RAR) in cancer cells, or treatment with a pan-RAR antagonist, dramatically reduces brain metastasis. Importantly, S100A9 expression in cancer cells correlates with poor PFS in osimertinib-treated patients. Our study, therefore, identifies a novel, therapeutically targetable S100A9-ALDH1A1-RA axis that drives brain relapse.SignificanceTreatment with the EGFR TKI osimertinib prolongs the survival of patients with EGFR-mutant lung cancer; however, patients develop metastatic relapses, often to the brain. We identified a novel intracellular S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and can be targeted by pan-RAR antagonists to prevent cancer progression and prolong patient survival. This article is highlighted in the In This Issue feature, p. 873.
| S-EPMC8983473 | biostudies-literature
Project description:Recombinant-murine S100A9 were used at 10 mg/50 ml in Hanks Balanced Salt solution (HBSS) or control HBSS administered onto the nares of BALB/C mice. To assess direct effects, mice were sacrificed 1, 4, 6, or 12 h post-inhalation of S100A9. Because S100A9 is reported to initiate proinflammatory responses by ligating TLR4 and/or RAGE, a quantitative PCR array was developed to analyze 49 genes, selected to reflect potential acute inflammatory changes induced by ligation of these receptors. Expression of inflammatory genes was evaluated with the RT-qPCR array. Relative quantities of mRNA in duplicate samples were obtained using the LightCycler® 480 Software 1.5 and the Efficiency-Method.
2016-08-01 | E-GEOD-74128 | biostudies-arrayexpress
Project description:Introduction: Overcoming of acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable obstacle for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are very complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR mutated lung cancer largely unknown. Methods: Osimertinib and afatinib-resistant EGFR-mutated lung cancer cells were established using by a stepwise method. Microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant NSCLC cells. Results: Microarray analysis was evaluated by bioinformatics analysis through medical-industrial collaboration. CRNDE and DGCR5 lncRNAs were highly expressed in EGFR-TKIs-resistant cells. CRNDE binds to eIF4A3 protein, down-regulates eIF4A3 and MUC1 expression, and down-regulates p-EGFR expression. CRNDE inhibition activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity and restored sensitivity to EGFR-TKIs. Conclusions: We identified lncRNA CRNDE associated with resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. CRNDE may be a novel therapeutic target for EGFR mutant NSCLC patients.
2021-04-28 | GSE163913 | GEO
Project description:Lung cancer is the leading cause of cancer related death worldwide, mainly due to the late stage of disease at the time of diagnosis. Non-invasive biomarkers are needed to supplement existing screening methods to enable earlier detection and increased patient survival. This is critical to EGFR-driven lung adenocarcinoma as it commonly occurs in individuals who have never smoked and do not qualify for current screening protocols. Methods: In this study, we performed mass spectrometry analysis of the secretome of cultured lung cells representing different stages of mutant EGFR driven transformation, from normal to fully malignant. Identified secreted proteins specific to the malignant state were validated using orthogonal methods and their clinical activity assessed in lung adenocarcinoma patient cohorts. Results: We quantified 1020 secreted proteins, which were compared for differential expression between stages of transformation. We validated differentially expressed proteins at the transcriptional level in clinical tumor specimens, association with patient survival, and absolute concentration to yield three biomarker candidates: MDK, GDF15, and SPINT2. These candidates were validated using ELISA and increased levels were associated with poor patient survival specifically in EGFR mutant lung adenocarcinoma patients. Conclusions: Our study provides insight into changes in secreted proteins during EGFR driven lung adenocarcinoma transformation that may play a role in the processes that promote tumor progression. The specific candidates identified can harnessed for biomarker use to identify high risk individuals for early detection screening programs and disease management for this molecular subgroup of lung adenocarcinoma patients.
2024-01-03 | PXD045328 | Pride
Project description:Brain metastasis significantly contributes to the failure of targeted therapy in patients with EGFR-mutated lung adenocarcinoma (LUAD). Reduced expression of RBM10 is associated with brain metastasis in these patients. However, the mechanism by which RBM10 affects brain metastasis in EGFR-mutated LUAD remains unclear. Previous studies reveal that RBM10 mutations lead to decreased expression and deregulated splicing at a subset of junctions, primarily through exon skipping.
2025-03-19 | GSE280915 | GEO
Project description:Recombinant-murine S100A9 were used at 10 mg/50 ml in Hanks Balanced Salt solution (HBSS) or control HBSS administered onto the nares of BALB/C mice. To assess direct effects, mice were sacrificed 1, 4, 6, or 12 h post-inhalation of S100A9. Because S100A9 is reported to initiate proinflammatory responses by ligating TLR4 and/or RAGE, a quantitative PCR array was developed to analyze 49 genes, selected to reflect potential acute inflammatory changes induced by ligation of these receptors.
2016-08-01 | GSE74128 | GEO
Project description:The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell lung cancer (NSCLC). Through comprehensive evaluation of potential drug resistance-imparting fusion oncogenes in EGFR mutant lung cancers, we selected candidate samples to be further validated by confirmatory assay. Here, we performed RNA sequencing as an unbiased genome-wide method to identify novel oncogenic fusions. In 11 samples from 10 patients, 3 different fusion callers consistently detected only the DLG1-BRAF fusion in sample 6. None of other putative fusions detected by DNA-based hybrid capture sequencing were validated.We concluded that only a subset of putative fusion was validated by RNA-seq.
2022-08-08 | GSE182323 | GEO
Project description:Oncogene-driven lung cancers such as those with activating mutations in the epidermal growth factor receptor (EGFR) often harbor additional co-occurring genetic alterations. The significance of most alterations co-occurring with mutant EGFR remains unclear. We report the impact of loss of the mRNA splicing factor RBM10 in human EGFR mutant lung cancer. RBM10 loss decreased EGFR inhibitor efficacy in patient-derived EGFR mutant tumor models. RBM10 regulated mRNA splicing of the mitochondrial apoptotic regulator Bcl-x. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by altering Bcl-x splicing, decreasing Bcl-xS (pro-apoptotic) and increasing Bcl-xL (anti-apoptotic) levels. Co-inhibition of Bcl-xL and mutant EGFR overcomes resistance induced by RBM10 loss. RBM10 loss was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Inactivation of the splicing factor RBM10 is a key co-occurring genetic alteration in EGFR mutant tumors that limits EGFR inhibitor efficacy and a potential biomarker of Bcl-xL inhibitor response.
2022-06-04 | GSE199240 | GEO
Project description:Fusion genes in EGFR mutant lung cancer
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