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The RNAseq of 79 small cell lung cancer (sclc) and 7 normal control

ABSTRACT: Even though small cell lung cancer (SCLC) has entered the age of broad genomic analysis, platinum-based chemotherapy remains the standard care for SCLC. Topotecan is the only approved agent for recurrent or progressive SCLC (1). In the absence of well-defined genomic biomarkers, clinical efficacy signals in genomically distinct subsets of SCLC could have been missed. Serine/Arginine Splicing Factor 1 (SRSF1) is a member of SR protein family. The deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers suggest that there are complex mechanisms and pathways underlying SRSF1-mediated transformation (2). Whole exome and transcriptome sequencing of primary tumor SCLC from 99 Chinese patients has identified SRSF1 DNA amplification and mRNA over-expression which predicts poor survival in Chinese SCLC patients. In vitro and in vivo studies have demonstrated that SRSF1 is essential for tumorigenecity of SCLC and plays a key role in DNA repair and chemo-sensitivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60052 | GEO | 2016/02/10

SECONDARY ACCESSION(S): PRJNA257389

REPOSITORIES: GEO

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The RNAseq of 79 small cell lung cancer (sclc) and 7 normal control

Project description:Even though small cell lung cancer (SCLC) has entered the age of broad genomic analysis, platinum-based chemotherapy remains the standard care for SCLC. Topotecan is the only approved agent for recurrent or progressive SCLC (1). In the absence of well-defined genomic biomarkers, clinical efficacy signals in genomically distinct subsets of SCLC could have been missed. Serine/Arginine Splicing Factor 1 (SRSF1) is a member of SR protein family. The deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers suggest that there are complex mechanisms and pathways underlying SRSF1-mediated transformation (2). Whole exome and transcriptome sequencing of primary tumor SCLC from 99 Chinese patients has identified SRSF1 DNA amplification and mRNA over-expression which predicts poor survival in Chinese SCLC patients. In vitro and in vivo studies have demonstrated that SRSF1 is essential for tumorigenecity of SCLC and plays a key role in DNA repair and chemo-sensitivity. We did RNAseq on 79 small cell lung cancer patients' tumor sample and 7 normal lung tissue. We normalized the RNAseq data and did differential expression analysis. The deleterious consequences of overexpression of the SRSF1 proto-oncogene in human cancers suggest that there are complex mechanisms and pathways underlying SRSF1-mediated transformation.

2016-02-10 | E-GEOD-60052 | biostudies-arrayexpress

99 Cases of Small Cell Lung Cancer Study

Project description:<p>Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.</p> <p>The manuscript has been accepted by Plos Genetics.</p>

| phs001083 | dbGaP

Unbiased proteomic profiling uncovers a targetable GNAS/PKA/PP2A axis in SCLC

Project description:Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, inhibits SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many new PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC cancer stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover novel targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.

2020-06-17 | PXD018209 | Pride

PAX5 promotes progression of SCLC

Project description:RNAseq of SCLC cell line H1155 with PAX5.knocked out. The goals of this study are to identify the function of PAX5 in SCLC.

2021-01-31 | GSE135439 | GEO

ChIP-seq of NeuroD1 and H3K4me3 in SCLC cells

Project description:We hypothesized that functional polymorphisms in NEUROD1 target genes may also affect the clinical outcomes of patients with SCLC, as NEUROD1 plays a crucial role in SCLC carcinogenesis. To test this hypothesis, we performed ChIP-seq of NeuroD1 and H3K4me3 in SCLC cells. Then we evaluated the association between putative functional polymorphisms in NEUROD1 target genes and the chemotherapy response and survival outcomes of patients with SCLC.

2022-08-19 | GSE211475 | GEO

PM01183 and Cisplatin on SCLC cell lines

Project description:Small Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes SCLC-A and SCLC-N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E-box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes such as BCL2, INSM1, MYC and AURKA, which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles' heel, and how this is effectively exploited by lurbinectedin as a novel and highly specific SCLC therapeutic endeavor.

2022-02-03 | GSE195663 | GEO

A PKA/PP2A AXIS DRIVES THE GROWTH OF NEUROENDOCRINE SCLC

Project description:Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer whose biology is still poorly understood. Using a multiplexed inhibitor beads assay, we identified active kinases in SCLC. Among those, we found that PKA is critical for the expansion of SCLC in culture and in vivo. PKA promotes the neuroendocrine epithelial state associated with SCLC tumor-initiating cells. Phosphoproteomics analyses identify ~200 PKA substrates and show that PKA controls multiple facets of SCLC growth. Notably, the PP2A phosphatase counteracts the oncogenic effects of PKA, and PP2A activators inhibit SCLC as single agents and with chemotherapy. Our data uncover key signaling networks in SCLC and indicate that targeting the PKA/PP2A pathway may help inhibit this lethal neuroendocrine cancer.

2020-02-11 | GSE126353 | GEO

RNAseq analysis of SCLC PDX models

Project description:We investigated the gene expression changes in a library of small cell lung carcinoma (SCLC) patient-derived xenograft (PDX) models.

2022-02-07 | E-MTAB-11230 | biostudies-arrayexpress

Identification of intrinsically immunogenic small cell lung carcinoma (SCLC) subpopulations

Project description:SCLC is molecularly and immunologically heterogenous. Here, using transcriptional and epigenomic profiling of plastic SCLC states in human and mouse cell lines, and patient samples, we define the phenotype of a SCLC population marked by increased MHC Class I antigen presentation.

2021-03-04 | GSE168195 | GEO

An ecosystem mimicking brain development promotes metastatic growth of SCLC in the brain

Project description:Small cell lung cancer (SCLC) is a fatal form of cancer that frequently metastasizes to the brain. Here we investigated the mechanisms allowing SCLC cells to grow in the unique brain microenvironment. We found that neuronal programs upregulated in SCLC cells during tumor progression and upon growth in the brain are critical for SCLC growth in the brain. Mechanistically, the presence of SCLC cells in the brain re-activates astrocytes, which in turn promote the survival of SCLC cells by secreting neuronal pro-survival factors such as SERPINE1. We also identified Reelin, a molecule produced by developing neurons to recruit astrocytes, as a molecule secreted by SCLC cells to recruit astrocytes to the tumor site and promote SCLC growth in the brain. Thus, SCLC cells co-opt mechanisms normally at play between astrocytes and neurons to promote SCLC growth in the brain. Targeting such developmental neuronal programs may help treat brain metastases.

2023-08-09 | GSE202233 | GEO

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