Project description:Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors.We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, typical and atypical carcinoid, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Pathway analysis of of CNV and gene expression data suggested deregulation of the NF-ĸB and MAPK/ERK pathways. This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.
Project description:The aim of this study was to perform a microarray analysis of the response pattern of EEC from both large and small bowel to infection in vitro, using Chlamydia trachomatis infection as a model. Two human EEC lines: LCC-18, derived from a neuroendocrine colonic tumour, and CNDT-2, derived from a small intestinal carcinoid, were infected with C. trachomatis serovar LGV II strain 434 (ATCC VR-902B). Penicillin G was used to induce persistent infection. Gene expression levels in infected and persistently infected EEC cells were investigated by microarray analysis
Project description:Tumor tissue of lung carcinoid tumors (pulmonary neuroendocrine tumors) and adjacent normal lung tissue was profiled using scRNA-seq
Project description:Molecular regulators of variably aggressive carcinoid tumors are unknown. Since carcinoids have low expression of Yes-associated protein (YAP), we hypothesized that low YAP expression provides a molecular advantage to carcinoids by preventing YAP from binding its partner, TEA domain transcription factor (TEAD). To test this hypothesis, we overexpressed constitutively active YAP and a TEAD-binding defective form of YAP in lung (H727) and pancreatic (BON1) carcinoid cells. We found that active YAP overexpression inhibited neuroendocrine markers, morphology, cell proliferation and anchorage-independent cell growth, while TEAD-binding defective YAP recovered these features. Through integrated ChIP-seq and RNA-seq analyses, we found that YAP-TEAD binding downregulated neuroendocrine transcription factor genes and upregulated transforming growth factor (TGFβ) and Notch genes related to cell growth. We conclude that low YAP expression permits neuroendocrine differentiation and growth in carcinoid cells by preventing YAP-TEAD binding and subsequent dysregulation of neuroendocrine transcription factors, TGFβ and Notch gene targets. These results identify unknown molecular mechanisms in carcinoid development that may apply to the broader family of neuroendocrine cancers.
Project description:We aimed to identify clinically meaningful biomarkers in pulmonary carcinoid tumors (PCTs), a member of neuroendocrine neoplasms, via profiling miRNAs and mRNAs.
Project description:Molecular regulators of variably aggressive carcinoid tumors are unknown. Since carcinoids have low expression of Yes-associated protein (YAP), we hypothesized that low YAP expression provides a molecular advantage to carcinoids by preventing YAP from binding its partner, TEA domain transcription factor (TEAD). To test this hypothesis, we overexpressed constitutively active YAP and a TEAD-binding defective form of YAP in lung (H727) and pancreatic (BON1) carcinoid cells. We found that active YAP overexpression inhibited neuroendocrine markers, morphology, cell proliferation and anchorage-independent cell growth, while TEAD-binding defective YAP recovered these features. Through integrated ChIP-seq and RNA-seq analyses, we found that YAP-TEAD binding downregulated neuroendocrine transcription factor genes and upregulated transforming growth factor (TGFβ) and Notch genes related to cell growth. We conclude that low YAP expression permits neuroendocrine differentiation and growth in carcinoid cells by preventing YAP-TEAD binding and subsequent dysregulation of neuroendocrine transcription factors, TGFβ and Notch gene targets. These results identify unknown molecular mechanisms in carcinoid development that may apply to the broader family of neuroendocrine cancers.
