Transcription elongation factors represent in vivo cancer dependencies in glioblastoma.

Nature
Authors
Keywords
Abstract

Glioblastoma is a universally lethal cancer with a median survival time of approximately 15 months. Despite substantial efforts to define druggable targets, there are no therapeutic options that notably extend the lifespan of patients with glioblastoma. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology for use in orthotopic patient-derived xenograft models, creating a high-throughput negative-selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators needed for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies, and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery may be an effective therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of 'cancer dependencies' not identified by previous in vitro approaches, and could supply new opportunities for therapeutic intervention.

Year of Publication
2017
Journal
Nature
Volume
547
Issue
7663
Pages
355-359
Date Published
2017 07 20
ISSN
1476-4687
DOI
10.1038/nature23000
PubMed ID
28678782
PubMed Central ID
PMC5896562
Links
Grant list
R01 CA169117 / CA / NCI NIH HHS / United States
CA169117 / NH / NIH HHS / United States
NS087913 / NH / NIH HHS / United States
CA183510 / NH / NIH HHS / United States
NS089272 / NH / NIH HHS / United States
P30 CA043703 / CA / NCI NIH HHS / United States
CA189647 / NH / NIH HHS / United States
CA197718 / NH / NIH HHS / United States
R01 CA171652 / CA / NCI NIH HHS / United States
R01 NS089272 / NS / NINDS NIH HHS / United States
R01 NS087913 / NS / NINDS NIH HHS / United States
R01 NS103434 / NS / NINDS NIH HHS / United States
R35 CA197718 / CA / NCI NIH HHS / United States
F32 CA189647 / CA / NCI NIH HHS / United States
F30 CA183510 / CA / NCI NIH HHS / United States
GM007250 / NH / NIH HHS / United States
T32 GM007250 / GM / NIGMS NIH HHS / United States
R01 CA154130 / CA / NCI NIH HHS / United States
CA171652 / NH / NIH HHS / United States
CA154130 / NH / NIH HHS / United States
F30 CA203101 / CA / NCI NIH HHS / United States