Project description:The genetic cause for PPB in association with renal tumor and small bowel polyps remains to be identified. Activation of components of the mTOR signalling pathway in the disease lesions suggests that this signal transduction route may be involved in disease pathogenesis and that rapamycin, an inhibitor of mTOR, might be effective in the treatment of PPB and associated lesions. A combination of molecular cytogenetics and gene-specific mutation screens were performed to search for an underlying genetic cause for PPB in association with small bowel polyps. Immunohistochemical analysis to measure mTOR activation was performed on tissue from renal and lung tumor and small bowel polyps from the index case
Project description:The genetic cause for PPB in association with renal tumor and small bowel polyps remains to be identified. Activation of components of the mTOR signalling pathway in the disease lesions suggests that this signal transduction route may be involved in disease pathogenesis and that rapamycin, an inhibitor of mTOR, might be effective in the treatment of PPB and associated lesions.
Project description:Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with highly regulated mesenchymal-epithelial interactions, a DICER1 mutation in PPB generates a faulty lung differentiation program with resultant biphasic tumors composed of a primitive epithelial and mesenchymal stroma with early progenitor blastomatous cells. Deciphering of PPB progression has been hampered by the difficulty of culturing PPB cells, and specifically progenitor blastomatous cells. Here we show that in contrast with in-vitro culture, establishment of PPB patient-derived xenograft (PDX) in NOD-SCID mice selects for highly proliferating progenitor blastoma overexpressing critical regulators of lung development and multiple imprinted genes. These stem-like tumors were sequentially interrogated by gene profiling to show a FGF module that is activated alongside Neural cell adhesion molecule 1 (NCAM1). Targeting the progenitor blastoma and these transitions with an anti-NCAM1 immunoconjugate (Lorvotuzumab-mertansine) inhibited tumor growth and progression providing new paradigms for PPB therapeutics. Altogether, we successfully establish a novel in-vivo model of PPB and uncover anti-NCAM1 as a potential therapeutic strategy for this aggressive malignancy.
Project description:<p>Pleuropulmonary blastoma (PPB) is a rare, aggressive pediatric cancer arising from the lung or pleural cavity. In this study, we sequenced and analyzed the exomes of 15 PPB matched tumor and normal pairs. This study is part of a larger effort to characterize pediatric cancers as part of the Slim Initiative for Genomic Medicine (SIGMA) project.</p>
Project description:Background: Pleuropulmonary blastoma (PPB) is a rare lung malignancy in children. Here, we classified PPB subpopulations with Single-cell RNA sequencing. Methods: This study included 10,007 single cells from a girl with PPB. After choosing malignant tumor cells with an inferring copy number variation, we used non-negative matrix factorization and Seurat analysis to cluster the cells and divided the subgroups by their differentially expressed genes and Gene Ontology enrichment analysis. Additionally, pseudotime trajectory analysis of PPB was conducted with Monocle. Results: Tumor cells were divided into muscle (DEShiTNNT1hiTNNI1hi) and cartilage (TWIST1hiHTRA1hiBMP4hi). In cartilage, SOX9hiPAX1hiPAX9hi prechondrocytes, OGNhiMGPhi chondrocytes and DKK2hi chondrocytes were defined. In muscle lineage, PAX7hiMYF5hi satellite myogenic cells and MYOGhiMEF2ChiMYOD1hi myocytes were defined. And a new undefined FABP7hi satellite cells subset was found to function like another known ITM2Ahi satellite cells subset. As the promoters of muscle cell development, both were responsible for establishing membrane protein and proliferating. Conclusions: Our results roughly defined muscle heterogeneity in PPB and found activated and proliferating FABP7 satellite myogenic cells. And these satellite cells might be activated by microRNA regulation induced by the mutation of PPB classic mutation gene DICER1.
Project description:Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. To better understand the biology of this tumor, we analyze the miRNA expression profiles of a set of CCPRCC by microarrays.
