Project description:We identify genes presenting a specific expression profile in midgut carcinoid cells, primary carcinoids tumors and liver metastasis were gene profiled. Gene expression profiling of classical midgut carcinoid primary tumors and liver metastasis reveal potential novel therapeutic targets and molecular signatures. Experiment Overall Design: Normal and tumoral (carcinoid) cells
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: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:Tumor tissue of lung carcinoid tumors (pulmonary neuroendocrine tumors) and adjacent normal lung tissue was profiled using scRNA-seq
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:This is an open-label phase II basket study evaluating the ability of enterade to reduce bowel frequency in neuroendocrine tumor (NET) patients with carcinoid syndrome and non-carcinoid syndrome.
Project description:We report RNA sequencing data for miR-375 knockout and YAP overexpression lung carcinoid cells (H727). Lung carcinoids are variably aggressive and mechanistically understudied neuroendocrine neoplasms (NENs). Here, we identified and elucidated the function of a miR-375/yes-associated protein (YAP) axis in lung carcinoid (H727) cells. miR-375 and YAP are respectively high and low expressed in wild-type H727 cells. Following lentiviral CRISPR/Cas9-mediated miR-375 depletion, we identified distinct transcriptomic changes including dramatic YAP upregulation. Similarly, YAP overexpression resulted in distinct and partially overlapping transcriptomic changes, phenocopying the effects of miR-375 depletion in the same models as above. Pathways analysis and confirmatory real-time PCR studies of shared dysregulated targets indicate that this axis controls neuroendocrine related functions such as neural differentiation, exocytosis, and secretion. Taken together, we provide compelling evidence that a miR-375/YAP axis is a critical mediator of neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.
Project description:We aimed to identify clinically meaningful biomarkers in pulmonary carcinoid tumors (PCTs), a member of neuroendocrine neoplasms, via profiling miRNAs and mRNAs.