Single-cell transcriptomics reveals tissue architecture in breast carcinosarcoma
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ABSTRACT: Breast carcinosarcoma is a rare and highly aggressive subtype of metaplastic breast cancer.Single-cell RNA sequencing revealed a heterogeneous cellular ecosystem within breast carcinosarcoma.
Project description:Ovarian carcinosarcoma (OCS) is one of rarest and most challenging histologic subtype of ovarian cancer. It features remarkable cellular heterogeneity. Using single-cell RNA sequencing, we characterize the cellular composition of the OCS and identify their molecular characteristics.
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.
Project description:Human breast cancers are broadly classified based on their gene expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast, luminal (EpCAM+) and basal/myoepithelial (ME, CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer including ER+ and ER- tumors with luminal and basal-like characteristics, respectively, while transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is due in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues. 8 breast cell line samples
Project description:In this study, we present a case of parotid gland de novo carcinosarcoma. Salivary gland carcinosarcoma (or true malignant mixed tumor) is a rare biphasic neoplasm, composed of both malignant epithelial and malignant mesenchymal components. It is yet unclear whether these two phenotypes occur by collision of two independent tumors or if they are of clonal origin. To analyze the clonality of the different morphologic tumor components, oligonucleotide microarray-based comparative genomic hybridization (oaCGH) was performed on the carcinoma and the sarcoma entity separately. This technique enables a high-resolution, genome-wide overview of the chromosomal alterations in the distinct tumor elements. Analysis of both fractions showed a high number of DNA copy number changes. Losses were more prevalent than gains (82 and 49, respectively). The carcinomatous element displayed more chromosomal aberrations than the sarcomatous component. Specific amplifications of MUC20 (in mesenchymal element) and BMI-1 (in both elements) loci were observed. Overall homology between the two genomic profiles was 75%. DNA copy number profiles of the epithelial and mesenchymal components in this salivary gland carcinosarcoma displayed extensive overlap, indicating a monoclonal origin. Since losses are shared to a larger extent than gains, they seem to be more essential for initial oncogenic events. Furthermore, specific amplifications of a mucin and a Polycomb group gene imply these proteins in the tumorigenesis of carcinosarcomas.
Project description:Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature revealed strong correlation with human MpBC tumors and MpBC xenograft (PDX) models. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC PDX tumorspheres revealed the therapeutic potential of targeting TRIM24. Altogether, global expression, single-cell immunophenotyping and mechanistic studies of tumors and MpBC PDX nominated TRIM24-activated c-MET/PI3K/mTOR pathways and TRIM24, which were validated as potential MpBC therapeutic targets.
Project description:Human breast cancers are broadly classified based on their gene expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast, luminal (EpCAM+) and basal/myoepithelial (ME, CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer including ER+ and ER- tumors with luminal and basal-like characteristics, respectively, while transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is due in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues.
Project description:Metaplastic breast cancer (MpBC) is a rare and aggressive form of breast cancer. Characteristically heterogeneous, MpBC are defined by the presence of various morphological elements, typically biphasic, with epithelial (e.g. non-special type (NST), squamous) and mesenchymal (e.g. spindle, chondroid, osteoid) components. The established clonality of the different components, favours an evolution model encompassing either a multipotent progenitor, or a linear metaplastic conversion. Our study defines the micro-methylome and a spatial transcriptomic profile in MpBC, and identifies potential drivers associated with tumor heterogeneity that supports the conversion model of metaplasia and warrants further functional analysis.
Project description:We performed genome-wide DNA methylation profiling of uterin and ovarian carcinosarcoma tissues derived from patients in the Cancer Institute Hospital of Japanese Foundation for Cancer Research.