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Stachler, Matthew

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Stachler

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Matthew

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Stachler, Matthew
Author's Publications: search.filters.isAuthorOfPublication.a4d57ab3-9301-4e55-badd-b1795f328221

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    Neonatal Fc Receptor Expression in Dendritic Cells Mediates Protective Immunity against Colorectal Cancer
    (Elsevier BV, 2013) Baker, Kristi; Rath, Timo; Flak, Magdalena B.; Arthur, Janelle C.; Chen, Zhangguo; Glickman, Jonathan; Zlobec, Inti; Karamitopoulou, Eva; Stachler, Matthew; Odze, Robert; Lencer, Wayne; Jobin, Christian; Blumberg, Richard
    Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8+ T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8+ T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8+ T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn–IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.
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    Src Mutation Induces Acquired Lapatinib Resistance in ERBB2-Amplified Human Gastroesophageal Adenocarcinoma Models
    (Public Library of Science, 2014) Hong, Yong Sang; Kim, Jihun; Pectasides, Eirini; Fox, Cameron; Hong, Seung-Woo; Ma, Qiuping; Wong, Gabrielle S.; Peng, Shouyong; Stachler, Matthew; Thorner, Aaron R.; Van Hummelen, Paul; Bass, Adam
    ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas. However, there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB2 inhibition. To investigate this question we sought to characterize cell line models of ERBB2-amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB2 inhibition. We generated lapatinib-resistant (LR) subclones from an initially lapatinib-sensitive ERBB2-amplified esophageal adenocarcinoma cell line, OE19. We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance. We identified a novel, acquired SrcE527K mutation in a subset of LR OE19 subclones. Cells with this mutant allele harbour increased Src phosphorylation. Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib. Biochemically, Src mutations could activate both the phosphatidylinositol 3-kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE19 cells. Ectopic expression of Src E527K mutation also was sufficient to induce lapatinib resistance in drug-naïve cells. These results indicate that pathologic activation of Src is a potential mechanism of acquired resistance to ERBB2 inhibition in ERBB2-amplified gastroesophageal cancer. Although Src mutation has not been described in primary tumor samples, we propose that the Src hyperactivation should be investigated in the settings of acquired resistance to ERBB2 inhibition in esophageal and gastric adenocarcinoma.
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    Paired Exome Analysis of Barrett’s Esophagus and Adenocarcinoma
    (2015) Stachler, Matthew; Taylor-Weiner, Amaro; Peng, Shouyong; McKenna, Aaron; Agoston, Agoston; Odze, Robert; Davison, Jon M.; Nason, Katie S.; Loda, Massimo; Leshchiner, Ignaty; Stewart, Chip; Stojanov, Petar; Seepo, Sara; Lawrence, Michael S.; Ferrer-Torres, Daysha; Lin, Jules; Chang, Andrew C.; Gabriel, Stacey B.; Lander, Eric S.; Beer, David G.; Getz, Gad; Carter, Scott; Bass, Adam J.
    Barrett’s esophagus, is thought to progress to esophageal adenocarcinoma (EAC) through a step-wise progression with loss of CDKN2A followed by p53 inactivation and aneuploidy. Here, we present whole exome sequencing from 25 pairs of EAC and Barrett’s and five patients whose Barrett’s and tumor were extensively sampled. Our analysis revealed that oncogene amplification typically occurred as a late event and that TP53 mutations often occur early in Barrett’s progression, including in non-dysplastic epithelium. Reanalysis of additional EAC exome data revealed that the majority (62.5%) of EACs emerged following genome doubling and that tumors with genomic doubling had different patterns of genomic alterations with more frequent oncogenic amplifications and less frequent inactivation of tumor suppressors, including CDKN2A. These data suggest that many EACs emerge not through gradual accumulation of tumor suppressor alterations but rather through a more direct path whereby a TP53-mutant cell undergoes genome doubling, followed by acquisition of oncogenic amplifications.