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FBXW7 is a defining driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

ABSTRACT: FBXW7 is a defining driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

PROVIDER: PRJNA576165 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10237653.fastq.gz	Fastqsanger.gz
	SRR10237654.fastq.gz	Fastqsanger.gz
	SRR10237655.fastq.gz	Fastqsanger.gz
	SRR10237656.fastq.gz	Fastqsanger.gz
	SRR10237657.fastq.gz	Fastqsanger.gz

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FBXW7 is a defining driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Project description:Fbxw7 is a tumor supressor frequently mutated in endometrial cancer. To analyze the signaling pathways that can be altered by Fbxw7 we compared RNA expression in the presence or absence of Fbxw7 in mouse endometrial cancer cells deficient for Fbxw7 and Pten.

2019-11-11 | GSE138490 | GEO

Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition.

Project description:Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial-mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.

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T-cell receptor repertoire in uterine and ovarian carcinosarcoma

Project description:Carcinosarcoma of the uterus or ovary is a rare, biphasic tumor comprising epithelial and mesenchymal elements, and exhibits aggressive clinical features. Four molecular subtypes of carcinosarcoma (POLE, MSI, CNH, and CNL) were recently established and shown to be associated with multiple clinicopathological parameters including patient outcomes. Immune microenvironment analyses on CS samples was performed using immune cell profiling with T-cell receptor repertoire assay. Carcinoma and sarcoma elements from CS samples were also assessed separately.

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FBXW7

Project description:FBXW7

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Project description:FBXW7 is a defining driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

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Whole-genome DNA methylation profiling identifies epigenetic signatures of uterine carcinosarcoma

Project description:Uterine carcinosarcoma (UCS) is a form of endometrial cancer simultaneously exhibiting carcinomatous and sarcomatous elements, but the underlying molecular and epigenetic characteristic of this disease is poorly understood. We generated complete DNA methylomes for both the carcinomatous and the sarcomatous components of three UCS samples separated by laser capture microdissection and compared DNA methylomes of UCS with that of normal endometrium as well as methylomes derived from endometrioid carcinoma, serous endometrial carcinoma, and endometrial stromal sarcoma. We identified epigenetic lesions specific to carcinosarcoma, and specific to two components. Hallmarks of DNA methylation abnormality of UCS included global hypomethylation, especially in repetitive elements, and hypermethylation of tumor suppressor gene promoters. Among these, aberrant DNA methylation of MIR200 genes is a key feature of UCS. The carcinoma component of UCS was characterized by hypermethylation of promoters of EMILIN1, NEFM and CLEC14A, genes that are associated with tumor vascularization. In contrast, DNA methylation changes of PKP3, FAM83F and TCP11 were more characteristic of the sarcoma components. Our findings highlight the epigenetic signatures that distinguish the two components of UCS, providing a valuable resource for investigation of these diseases.

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FBXW7

Project description:Purpose: FBXW7 is one of the most frequently mutated tumor suppressors, the deficiency of which has been associated with resistance to some anticancer therapies. Through bioinformatic analyses and genome-wide CRISPR screens, we here reveal that FBXW7 deficiency leads to multi-drug resistance (MDR), to a bigger extent than well-established MDR-drivers such as ABCB1. Proteomic data from FBXW7-deficient cells and human cancer samples identify the upregulation of mitochondrial function as a hallmark of FBXW7 deficiency, which has been previously linked to an increased resistance to chemotherapy. Accordingly, genetic or chemical targeting of mitochondria is preferentially toxic for FBXW7-deficient cells. For instance, targeting mitochondrial translation with the antibiotic Tigecycline efficiently kills FBXW7-deficient cells in vitro and in vivo, by a mechanism that involves activation of the Integrated Stress Response (ISR). Searching for additional drugs that overcome MDR in FBXW7-deficient cells, we found several targeted therapies such as Erlotinib, Dasatinib or Vemurafenib which unexpectedly also activate the ISR. Together, our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance. Methods: This study was performed in 2 groups of DLD1 cells with duplicate samples per group. Both control (Wild Type, WT) and experimental (FBXW7 -/-, KO) were exposed to Tigecycline (10µM). DMSO was used as a control for the treatment. After 24h, the RNA was extracted and the transcriptome was profiled with RNA-Sequencing (RNA-seq) analysis. Results: our study reveals that one of the most frequent mutations in cancer reduces the sensitivity to the vast majority of available therapies, and identifies a general principle to overcome such resistance.

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Transcriptome data of uterine and ovarian carcinosarcoma tissues derived from patients in the Cancer Institute Hospital of Japanese Foundation for Cancer Research

Project description:We performed RNA-seq experiments for total RNA of uterin and ovarian carcinosarcoma tissues.

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Effect of FBXW7 loss and concomitant FBXW7-KMT2D loss on mRNA levels

Project description:We assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. This experiment assesses the role of the FBXW7-KMT2D axis in regulating gene expression in OPM-1 cells.

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T-cell receptor repertoire in uterine and ovarian carcinosarcoma

Project description:T-cell receptor repertoire in uterine and ovarian carcinosarcoma

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