4 research outputs found
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Clinical features of brain metastasis from salivary gland tumors
Salivary gland tumors comprise a group of 24 tumor subtypes with a wide range of clinical behaviors and propensities for metastasis. Several prognostic factors have been identified that help predict the development of systemic metastases, most commonly to the lung, liver, or bone. Metastases to the brain are rare. To better understand the behavior of salivary gland tumors that metastasise to the brain, we performed a retrospective cohort analysis on a series of patients to highlight features of their medical and surgical management. From 2007 to 2011, a database of 4117 elective craniotomies were queried at a single institution to identify patients surgically treated for salivary gland metastases to the brain. Three patients were identified. Histologic subtypes included salivary duct carcinoma, poorly differentiated carcinoma, and papillary mucinous adenocarcinoma. They had all undergone previous treatment for their primary malignancy. The mean time to intracranial metastasis was 48 months from initial diagnosis (range, 14–91 months). Treatment for intracranial metastases included surgical resection, whole brain radiation, stereotactic radiosurgery, and chemotherapy. Intracranial metastases from salivary gland tumors are rare, present years after diagnosis of the primary tumor, and are treatable with multimodality therapy
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Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma
Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single cell RNA-seq to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy
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Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells
Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance, yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements, and are sufficient to fully reprogram differentiated GBM cells to ‘induced’ TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies novel therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies
Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq
Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME).We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.National Cancer Institute (U.S.) (Grant P30-CA14051