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1.
Cell Rep ; 4(6): 1116-30, 2013 Sep 26.
Article in English | MEDLINE | ID: mdl-24055055

ABSTRACT

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Adaptor Proteins, Signal Transducing/genetics , Alleles , Animals , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Estradiol/pharmacology , Female , Gene Amplification , Genomic Instability , Heterografts , Humans , Mice , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Staging , Phosphoproteins/genetics , Point Mutation , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/genetics , Transcription Factors , Translocation, Genetic , YAP-Signaling Proteins
2.
J Immunol ; 185(9): 4983-7, 2010 Nov 01.
Article in English | MEDLINE | ID: mdl-20876348

ABSTRACT

The increasing prevalence of atopy and asthma remains unexplained but may be due to infection with respiratory viruses. In support of this hypothesis, we showed that experimental asthma after viral infection in mice depended on type I IFN-driven upregulation of FcεRI on conventional dendritic cells (cDCs) in the lung. In this article, we demonstrate that FcεRI expression on lung cDCs depends on an unexpected activity of a CD49d(+) subset of polymorphonuclear neutrophils (PMNs) that are found in the lungs of wild-type C57BL6 but not mice deficient in type I IFNR. Expression of FcεRI depends in part on a CD11b-dependent interaction between PMNs and cDCs. This study demonstrates a PMN-cDC interaction in the lung that is necessary for the ability of viral infection to induce atopic disease.


Subject(s)
Asthma/immunology , Dendritic Cells/immunology , Integrin alpha4/immunology , Neutrophils/immunology , Receptors, IgE/immunology , Animals , Asthma/virology , Cell Separation , Cells, Cultured , Dendritic Cells/metabolism , Disease Models, Animal , Flow Cytometry , Immunohistochemistry , Integrin alpha4/biosynthesis , Lung/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/metabolism , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/immunology , Receptors, IgE/biosynthesis , Respiratory Tract Infections/complications , Respiratory Tract Infections/immunology , Respirovirus Infections/complications , Respirovirus Infections/immunology , Reverse Transcriptase Polymerase Chain Reaction , Sendai virus
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