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Stiles, Charles

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Stiles

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Charles

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Stiles, Charles
Author's Publications: search.filters.isAuthorOfPublication.23b0f6b2-7925-4ee5-88b8-51bd949fa65a

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    Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
    (eLife Sciences Publications, Ltd, 2017) Paolella, Brenton R.; Gibson, William; Urbanski, Laura M; Alberta, John; Zack, Travis Ian; Bandopadhayay, Pratiti; Nichols, Caitlin; Agarwalla, Pankaj Kumar; Brown, Meredith S; Lamothe, Rebecca; Yu, Yong; Choi, Peter; Obeng, Esther A; Heckl, Dirk; Wei, Guo; Wang, Belinda; Tsherniak, Aviad; Vazquez, Francisca; Weir, Barbara Ann; Root, David E; Cowley, Glenn S; Buhrlage, Sara; Stiles, Charles; Ebert, Benjamin; Hahn, William; Reed, Robin; Beroukhim, Rameen
    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. DOI: http://dx.doi.org/10.7554/eLife.23268.001
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    Molecular imaging of drug transit through the blood-brain barrier with MALDI mass spectrometry imaging
    (Nature Publishing Group, 2013) Liu, Xiaohui; Ide, Jennifer L.; Norton, Isaiah Hakim; Marchionni, Mark A.; Ebling, Maritza C.; Wang, Lan; Davis, Erin; Sauvageot, Claire M.; Kesari, Santosh; Kellersberger, Katherine A.; Easterling, Michael L.; Santagata, Sandro; Stuart, Darrin D.; Alberta, John; Agar, Jeffrey N.; Stiles, Charles; Agar, Nathalie Y. R.
    Drug transit through the blood-brain barrier (BBB) is essential for therapeutic responses in malignant glioma. Conventional methods for assessment of BBB penetrance require synthesis of isotopically labeled drug derivatives. Here, we report a new methodology using matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) to visualize drug penetration in brain tissue without molecular labeling. In studies summarized here, we first validate heme as a simple and robust MALDI MSI marker for the lumen of blood vessels in the brain. We go on to provide three examples of how MALDI MSI can provide chemical and biological insights into BBB penetrance and metabolism of small molecule signal transduction inhibitors in the brain – insights that would be difficult or impossible to extract by use of radiolabeled compounds.
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    Identification of Molecular Compartments and Genetic Circuitry in the Developing Mammalian Kidney
    (Company of Biologists, 2012) Duah, Mary; Staser, Karl; Valerius, Michael; Hansard, Jennifer K.; Guo, Jin-jin; McMahon, Jill Ann; Vaughan, Joseph; Faria, Diane; Georgas, Kylie; Rumballe, Bree; Ren, Qun; Krautzberger, A. Michaela; Junker, Jan P.; Thiagarajan, Rathi D.; Machanick, Philip; Gray, Paul A.; van Oudenaarden, Alexander; Rowitch, David H.; Stiles, Charles; Ma, Qiufu; Grimmond, Sean M.; Bailey, Timothy L.; Little, Melissa H.; McMahon, Andrew P.; Yu, Jing
    Lengthy developmental programs generate cell diversity within an organotypic framework, enabling the later physiological actions of each organ system. Cell identity, cell diversity and cell function are determined by cell type-specific transcriptional programs; consequently, transcriptional regulatory factors are useful markers of emerging cellular complexity, and their expression patterns provide insights into the regulatory mechanisms at play. We performed a comprehensive genome-scale in situ expression screen of 921 transcriptional regulators in the developing mammalian urogenital system. Focusing on the kidney, analysis of regional-specific expression patterns identified novel markers and cell types associated with development and patterning of the urinary system. Furthermore, promoter analysis of synexpressed genes predicts transcriptional control mechanisms that regulate cell differentiation. The annotated informational resource (www.gudmap.org) will facilitate functional analysis of the mammalian kidney and provides useful information for the generation of novel genetic tools to manipulate emerging cell populations.
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    A Genome-Wide In Situ Hybridization Map of RNA-Binding Proteins reveals Anatomically Restricted Expression in the Developing Mouse Brain
    (BioMed Central, 2005) McKee, Adrienne E.; Minet, Emmanuel; Stern, Charlene; Riahi, Shervin; Stiles, Charles; Silver, Pamela
    Background: In eukaryotic cells, RNA-binding proteins (RBPs) contribute to gene expression by regulating the form, abundance, and stability of both coding and non-coding RNA. In the vertebrate brain, RBPs account for many distinctive features of RNA processing such as activity-dependent transcript localization and localized protein synthesis. Several RBPs with activities that are important for the proper function of adult brain have been identified, but how many RBPs exist and where these genes are expressed in the developing brain is uncharacterized. Results: Here we describe a comprehensive catalogue of the unique RBPs encoded in the mouse genome and provide an online database of RBP expression in developing brain. We identified 380 putative RBPs in the mouse genome. Using in situ hybridization, we visualized the expression of 323 of these RBP genes in the brains of developing mice at embryonic day 13.5, when critical fate choice decisions are made and at P0, when major structural components of the adult brain are apparent. We demonstrate i) that 16 of the 323 RBPs examined show neural-specific expression at the stages we examined, and ii) that a far larger subset (221) shows regionally restricted expression in the brain. Of the regionally restricted RBPs, we describe one group that is preferentially expressed in the E13.5 ventricular areas and a second group that shows spatially restricted expression in postmitotic regions of the embryonic brain. Additionally, we find a subset of RBPs that share the same complex pattern of expression, in proliferating regions of the embryonic and postnatal NS and peripheral tissues. Conclusion: Our data show that, in contrast to their proposed ubiquitous involvement in gene regulation, most RBPs are not uniformly expressed. Here we demonstrate the region-specific expression of RBPs in proliferating vs. post-mitotic brain regions as well as cell-type- pecific RBP expression. We identify uncharacterized RBPs that exhibit neural-specific expression as well as novel RBPs that show expression in non-neural tissues. The data presented here and in an online database provide a visual filter for the functional analysis of individual RBPs.
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    Profiling Critical Cancer Gene Mutations in Clinical Tumor Samples
    (Public Library of Science, 2009) Campbell, Catarina D.; Kehoe, Sarah M.; Hatton, Charles; Niu, Lili; Yao, Keluo; Hanna, Megan; Mondal, Chandrani; Luongo, Lauren; Baker, Alissa C.; Philips, Juliet; Goff, Deborah J.; Rubin, Mark A.; Corso, Gianni; Roviello, Franco; MacConaill, Laura; Bass, Adam; Davis, Matt; Emery, Caroline Margaret; Fiorentino, Michelangelo; Polyak, Kornelia; Chan, Jennifer; Wang, Yufang; Fletcher, Jonathan; Santagata, Sandro; Shivdasani, Ramesh; Kieran, Mark W.; Ligon, Keith; Stiles, Charles; Hahn, William; Meyerson, Matthew; Garraway, Levi; Jones, Chris
    Background: Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach. We report the implementation of a genotyping and validation algorithm that enables robust tumor mutation profiling in the clinical setting. Methodology: We developed and implemented an optimized mutation profiling platform (“OncoMap”) to interrogate ∼400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies. The performance of OncoMap was analyzed using DNA derived from both frozen and FFPE clinical material in a diverse set of cancer types. A subsequent in-depth analysis was conducted on histologically and clinically annotated pediatric gliomas. The sensitivity and specificity of OncoMap were 93.8% and 100% in fresh frozen tissue; and 89.3% and 99.4% in FFPE-derived DNA. We detected known mutations at the expected frequencies in common cancers, as well as novel mutations in adult and pediatric cancers that are likely to predict heightened response or resistance to existing or developmental cancer therapies. OncoMap profiles also support a new molecular stratification of pediatric low-grade gliomas based on BRAF mutations that may have immediate clinical impact. Conclusions: Our results demonstrate the clinical feasibility of high-throughput mutation profiling to query a large panel of “actionable” cancer gene mutations. In the future, this type of approach may be incorporated into both cancer epidemiologic studies and clinical decision making to specify the use of many targeted anticancer agents.