Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE23768
PROVIDER: PRJNA133063 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To characterize the effects of common ALK fusion genes, we performed a comprehensive RNA-Seq analysis of NL20 cells induced with ALK-EML4-V1, ALK-EML4-V3, ALK-TFG, ALK-KIF5B, using Doxycycline
2022-12-18 | E-MTAB-11304 | biostudies-arrayexpress
Project description:Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNAseq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-B and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
2023-02-16 | PXD035100 | Pride
Project description:Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated -galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. Conclusions: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.
2021-01-20 | GSE165137 | GEO
Project description:Oncogenic fusions of EML4 and ALK occur in ~5% of lung adenocarcinomas. EML4- ALK variants have distinct breakpoints within EML4, but the functional differences among these variants remain poorly understood. Here we use CRISPR/Cas9 somatic genome editing to generate autochthonous mouse models of the two most common EML4-ALK variants and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth in vivo we show that many tumor suppressor genes have dramatically variant-specific effects on tumorigenesis. Pharmacogenomic analyses suggest that tumor genotype can also modify responses to therapy. Analysis of a large human EML4-ALK lung cancer cohort identified differences in the genomic landscape depending on the EML4-ALK variant. These findings demonstrate functional heterogeneity between EML4-ALK variants, suggesting that EML4-ALK variants behave more like distinct oncogenes than a uniform entity. More broadly, these findings highlight the dramatic impact of oncogenic fusions partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion driven cancer.
2025-08-06 | GSE301214 | GEO
Project description:Oncogenic fusions of EML4 and ALK occur in ~5% of lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but the functional differences among these variants remain poorly understood. Here we use CRISPR/Cas9 somatic genome editing to generate autochthonous mouse models of the two most common EML4-ALK variants and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth in vivo we show that many tumor suppressor genes have dramatically variant-specific effects on tumorigenesis. Pharmacogenomic analyses suggest that tumor genotype can also modify responses to therapy. Analysis of a large human EML4-ALK lung cancer cohort identified differences in the genomic landscape depending on the EML4-ALK variant. These findings demonstrate functional heterogeneity between EML4-ALK variants, suggesting that EML4-ALK variants behave more like distinct oncogenes than a uniform entity. More broadly, these findings highlight the dramatic impact of oncogenic fusions partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion driven cancer.
2025-08-12 | GSE302650 | GEO
Project description:First line treatment for EML4-ALK fusion-positive lung cancer patient is the use of an ALK tyrosine kinase inhibitor (TKI), such as alectinib. While most patients initially respond to this therapy, many patients often develop relapse, and efficacious therapies for patients with relapse disease are limited. To study EML4-ALK fusion-positive lung cancer, novel murine lung cancer cell lines were generated from C57BL/6 mice using an intratracheally injected Adeno-virus that contains Cas9 and guide RNAs for the EML4-ALK translocation, which leads to the development of lung tumors. Cell lines were derived from these tumors. In an effort to better understand how cells respond to alectinib, we treated EML4-ALK-positive murine cell lines (EA1, EA2, and EA3 cells) in vitro for 1-7 days with either 100nM alectinib or DMSO-control. At each time point, RNA was isolated from each condition. RNA was submitted to RNA-seq. Differential analysis on the RNA-seq data was performed to determine and track gene changes over time between control and treated cells. These data will allow us to better develop novel therapeutics to use in conjunction with alectinib when treating EML4-ALK fusion-positive patients.
2022-11-05 | GSE217115 | GEO
Project description:Acquired resistance to ALKi in NSCLC patients is attributed to gain of mutations in the ALK-EML4 fusion gene and an enhancement of the EGFR and/or IGF1R pathways. Here, we explain the epigenetic change that drives the EGFR and IGF1R reactivation in the absence of the appearance of an ALK-EML4 mutated scenario.
2021-02-01 | GSE78217 | GEO
Project description:We demonstrate that EML4-ALK siRNAs significantly reduced cell viability in EML4-ALK postive lung cancer cell lines,while overexpression of EML4-ALK increased cell viability in HEK293 cells in vitro. The aim of this study was to analyze the EML4-ALK regulated gene expression in lung cancer.
2021-05-20 | GSE174772 | GEO
Project description:Heat Shock Protein 90 inhibitors (HSP90i) have shown encouraging activity in EML4-ALK+ non-small cell lung cancer (NSCLC) patients but clinical responses have been heterogeneous. It has been suggested that distinct EML4-ALK variants may have a differential impact on the response to HSP90 inhibition. Here, we show that NSCLC cells harboring the most common EML4-ALK variant 1 (v1) or variant 3 (v3) are similarly sensitive to HSP90i. To discover new genetic alterations that could be involved in stratifying sensitivity, we performed a genome-wide CRISPR/Cas9 knockout screen and found that loss of Spindly increases the sensitivity of EML4-ALK v3, but not v1, NSCLC cells to low concentrations of HSP90i from three distinct chemical families. Upon loss of Spindly, prolonged exposure to low concentrations of HSP90i impairs chromosome congression and cellular fitness. Collectively, our data suggest that mutations leading to loss of Spindly in EML4-ALK v3 NSCLC patients may increase sensitivity to low doses of HSP90i.
2025-02-01 | GSE197655 | GEO
Project description:Identification of genes up-regulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. To elucidate molecular characteristics of lung adenocarcinomas (ADCs) with ALK mutations and those without EGFR, KRAS and ALK mutations, 226 primary lung ADCs of pathological stage I-II, examined for the status of EGFR, KRAS and ALK mutations, were subjected to genome-wide expression profiling, and genes up-regulated in lung ADCs with ALK mutations and those without EGFR, KRAS and ALK mutations were identified. One hundred and seventy-four genes, including ALK, were selected as being up-regulated specifically in 79 lung ADCs without EGFR and KRAS mutations. These 79 cases were divided into: 11 cases of ALK-positive ADCs, 36 cases of group A triple-negative ADCs, and 32 cases of group B triple-negative ADCs, by unsupervised clustering according to the expression of the 174 genes. In ALK-positive ADCs, 30 genes, including ALK itself and GRIN2A, were significantly overexpressed. Group A triple-negative ADC cases showed significantly worse prognoses for relapse and death than ADC cases with EGFR, KRAS or ALK mutations and group B triple-negative ADC cases. Nine genes were identified as being significantly up-regulated in group A triple-negative ADC cases and critical for predicting their prognosis. The nine genes included DEPDC1, which had been identified as a candidate diagnostic and therapeutic target in bladder and breast cancers. Genes discriminating this group of ADCs will be useful for selection of patients who will benefit from adjuvant chemotherapy after surgical resection of stage I-II triple-negative ADCs and also informative for the development of molecular targeting therapies for these patients. Expression profiles in of 226 lung adenocarcinomas (127 with EGFR mutation, 20 with KRAS mutation, 11 with EML4-ALK fusion and 68 triple negative cases).
2011-11-01 | E-GEOD-31210 | biostudies-arrayexpress