Normal adult liver is uniquely capable of renewal
Restoration of liver mass after injury requires proliferative and not embryonic transcriptional patterns.
Age
View SamplesWe generated gene expression profiles of 5 time points in murine lung development (E11.5, E13.5, E14.5, E16.5 and P5). The goal of this study was to establish a reference data set for exploration of large-scale similarities between transcriptomes in development and cancer.
Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers.
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View SamplesGenomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of human cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes tested regulate proliferation, many performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in SCNAs (somatic copy number changes) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue type-specific genetic network architectures underlie SCNA selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive new insights about the genetic network architecture of aneuploidy in tumors. KRTAPs are a class of human genes that promote proliferation in mammary epithelial cells (HMEC), but the mechanism is not understood. We performed RNAseq to study transcriptional changes associated with oeverxepression of KRTAPs and other oncogenes in hTERT-immortalized human mammary epithelial cells. GSEA analysis revealed the top enriched pathways upregulated by KRTAP expression are E2F-mediated regulation of DNA replication, G1-S specific transcription, cell cycle, translation and ribosome. KRTAP-induced mRNA changes are most closely related to those due to CCND1 expression, including induction of E2F1 transcription factor. Overall design: Analysis of whole transcriptome in HMEC overexpressing different human genes.
Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns.
Specimen part, Disease, Subject
View SamplesBackground: Central nervous system (CNS) metastases represent a major problem in the treatment of HER2-positive breast cancer due to the disappointing efficacy of HER2-targeted therapies in the brain microenvironment. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in preclinical models of brain metastases.
Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment.
Specimen part, Disease, Time
View SamplesComparative analysis of FACS-sorted CCR2- and CCR2+ HSC in the steady state. CCR2+ HSC have fourfold higher proliferative rates than CCR2- HSC, are are biased towards the myeloid lineage and dominate the migratory HSC population.
Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells.
Specimen part
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