Project description:In this study we have sequenced the ctDNA of 28 Small Cell Lung Cancer patients in the TP53 gene, each sample has been sequenced twice.
Project description:There are few effective treatments for small cell lung cancer (SCLC). We explored a major dependency of small cell lung cancer as a therapeutic target. Nearly all of SCLCs have telomerase activity and they are dependent on this enzyme for their ability to continuously divide. We utilized a nucleoside analog, 6-Thio-2’-deoxyguanosine (6TdG), that is preferentially recognized by telomerase to promote telomere dysfunction. Low and intermittent doses of 6TdG inhibited tumor growth and metastasis from the primary tumors. Anti-tumor activity of 6TdG was associated with decrease in cancer initiation cell (CIC) markers L1CAM/CD133 and increase in visibility to innate and adaptive immunity. Mechanistically, 6TdG depleted CICs and induced type-I interferon signaling by activating tumor STING. We confirmed the functional essential role of CIC markers L1CAM/CD133 in SCLC tumor initiation. We also observed dramatic synergy between 6TdG and irradiation in both syngeneic and humanized SCLC models that was dependent on immune cells.
Project description:We sequenced mammary gland samples of MMTV-PyMT mouse from 4 stages (hyperplasia at week 6, adenoma/MIN at week 8, early carcinoma at week 10, and late carcinoma with lung metastasis at week 12) during tumor progression. We sacrificed 3 PyMT (FVB background) mice and 3 FVB control mice at each of the 4 stages, extracted small RNA and performed sequencing.
Project description:Endothelial cells of blood vessel playing a key role in the metastasis of tumor cells particularly the brain microvascular endothelial cells in the brain-tropic metastasis of lung tumor cells. Currently, studies towards the influence contributed by tumor cells to the alteration of endothelial cells have been extensively conducted by contrast studies for the alteration of gene-expression signature of tumor cells under the influence of endothelial cells remains poorly characterized, thus in this study the transcriptome of the human small-cell lung cancer cell NCI-H209 was sequenced via RNA-Seq after conditioned by human brain microvascular endothelial cell (HBMEC) for characterizing the alteration of gene-expression signature.
Project description:The enhanced metastatic ability of small-cell lung cancer warrants the discovery of prognostic biomarkers to support decisions during the course of the disease. We have previously demonstrated the clinical significance of JUNB and CXCR4 expression in circulating tumor cells (CTCs) from breast and non-small cell lung cancer (NSCLC). patients. In the present study, we aimed to explore the expression levels of the aforementioned biomarkers in patients’ CTCs and plasma-derived exosomes. One hundred SCLC patients at baseline were enrolled in the study; exosome isolation was performed in 58 of them. Cytospins were analyzed using the VyCAP system and exosomes were characterized based on their molecular and transcriptomic profile. JUNB and CXCR4 were expressed in the majority of the CTCs. Protein exosomal expression of both biomarkers in patients was significantly different compared to healthy donors (p = 0.003 and p = 0.027, respectively), while a high discriminative ability was observed in patients overexpressing JUNB and CXCR4 in their exosomes (c-statistic = 0.949 and c-statistic = 0.903 respectively). The presence of JUNB and/or CXCR4 in CTCs was associated with poorer OS (p = 0.025). CXCR4 exosomal overexpression correlated with the presence of CTCs and their phenotypes. Lastly, miRNA profiling on 4 SCLC patients, indicated a multitude of biological processes and signaling pathways implicated in SCLC pathogenesis. Our study is the first attempt to evaluate two different aspects of liquid biopsy (CTCs and exosomes) in SCLC patients, regarding JUNB and CXCR4 expression, aiming to provide a potential new prognostic and/ or diagnostic approach.
Project description:In a stepwise approach, we evaluated available protocols before performing an analysis on circulating tumor cells of small cell lung cancer patients. We first compared 19 protocols on single MCF7 cells spiked miRExplore. Second, we analyzed MCF7 single cell equivalents of the eight best protocols. Third, we carried out single cell small RNA sequencing using the best performing protocol on 8 cell lines and 67 circulating tumor cells from seven small cell lung cancer patients.
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.
Project description:Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for new targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inhibitor of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes suggesting this may be used as a predictive biomarker of activity. The targeted mechanism coupled with a novel predictive biomarker make LSD1 inhibition an exciting potential therapy for SCLC, a highly prevalent, rarely cured, tumor type representing approximately 15% of all lung cancers. DNA methylation profiling was performed using Infinium 450K methylation arrays on SCLC cell lines, patient derived xenografts, and patient samples. Data was processed and normalized using GenomeStudio V2011.1