Dataset Information

Next-generation characterization of the Cancer Cell Line Encyclopedia.

ABSTRACT: Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.

SUBMITTER: Ghandi M

PROVIDER: S-EPMC6697103 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Next-generation characterization of the Cancer Cell Line Encyclopedia.

Ghandi Mahmoud M Huang Franklin W FW Jané-Valbuena Judit J Kryukov Gregory V GV Lo Christopher C CC McDonald E Robert ER Barretina Jordi J Gelfand Ellen T ET Bielski Craig M CM Li Haoxin H Hu Kevin K Andreev-Drakhlin Alexander Y AY Kim Jaegil J Hess Julian M JM Haas Brian J BJ Aguet François F Weir Barbara A BA Rothberg Michael V MV Paolella Brenton R BR Lawrence Michael S MS Akbani Rehan R Lu Yiling Y Tiv Hong L HL Gokhale Prafulla C PC de Weck Antoine A Mansour Ali Amin AA Oh Coyin C Shih Juliann J Hadi Kevin K Rosen Yanay Y Bistline Jonathan J Venkatesan Kavitha K Reddy Anupama A Sonkin Dmitriy D Liu Manway M Lehar Joseph J Korn Joshua M JM Porter Dale A DA Jones Michael D MD Golji Javad J Caponigro Giordano G Taylor Jordan E JE Dunning Caitlin M CM Creech Amanda L AL Warren Allison C AC McFarland James M JM Zamanighomi Mahdi M Kauffmann Audrey A Stransky Nicolas N Imielinski Marcin M Maruvka Yosef E YE Cherniack Andrew D AD Tsherniak Aviad A Vazquez Francisca F Jaffe Jacob D JD Lane Andrew A AA Weinstock David M DM Johannessen Cory M CM Morrissey Michael P MP Stegmeier Frank F Schlegel Robert R Hahn William C WC Getz Gad G Mills Gordon B GB Boehm Jesse S JS Golub Todd R TR Garraway Levi A LA Sellers William R WR

Nature 20190508 7757

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to ...[more]

PMID: 31068700

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Project description:UnlabelledUsing high-throughput RNA sequencing data from 50 common lymphoma cell culture models from the Cancer Cell Line Encyclopedia project, we performed an unbiased global interrogation for the presence of a panel of 740 viruses and strains known to infect human and other mammalian cells. This led to the findings of previously identified infections by Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and human T-lymphotropic virus type 1 (HTLV-1). In addition, we also found a previously unreported infection of one cell line (DEL) with a murine leukemia virus. High expression of murine leukemia virus (MuLV) transcripts was observed in DEL cells, and we identified four transcriptionally active integration sites, one being in the TNFRSF6B gene. We also found low levels of MuLV reads in a number of other cell lines and provided evidence suggesting cross-contamination during sequencing. Analysis of HTLV-1 integrations in two cell lines, HuT 102 and MJ, identified 14 and 66 transcriptionally active integration sites with potentially activating integrations in immune regulatory genes, including interleukin-15 (IL-15), IL-6ST, STAT5B, HIVEP1, and IL-9R. Although KSHV and EBV do not typically integrate into the genome, we investigated a previously identified integration of EBV into the BACH2 locus in Raji cells. This analysis identified a BACH2 disruption mechanism involving splice donor sequestration. Through viral gene expression analysis, we detected expression of stable intronic RNAs from the EBV BamHI W repeats that may be part of long transcripts spanning the repeat region. We also observed transcripts at the EBV vIL-10 locus exclusively in the Hodgkin's lymphoma cell line, Hs 611.T, the expression of which were uncoupled from other lytic genes. Assessment of the KSHV viral transcriptome in BCP-1 cells showed expression of the viral immune regulators, K2/vIL-6, K4/vIL-8-like vCCL1, and K5/E2-ubiquitin ligase 1 that was significantly higher than expression of the latency-associated nuclear antigen. Together, this investigation sheds light into the virus composition across these lymphoma model systems and provides insights into common viral mechanistic principles.ImportanceViruses cause cancer in humans. In lymphomas the Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV) and human T-lymphotropic virus type 1 are major contributors to oncogenesis. We assessed virus-host interactions using a high throughput sequencing method that facilitates the discovery of new virus-host associations and the investigation into how the viruses alter their host environment. We found a previously unknown murine leukemia virus infection in one cell line. We identified cellular genes, including cytokine regulators, that are disrupted by virus integration, and we determined mechanisms through which virus integration causes deregulation of cellular gene expression. Investigation into the KSHV transcriptome in the BCP-1 cell line revealed high-level expression of immune signaling genes. EBV transcriptome analysis showed expression of vIL-10 transcripts in a Hodgkin's lymphoma that was uncoupled from lytic genes. These findings illustrate unique mechanisms of viral gene regulation and to the importance of virus-mediated host immune signaling in lymphomas.

Dataset Information

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Publications

Next-generation characterization of the Cancer Cell Line Encyclopedia.

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