Journal
SCIENCE
Volume 373, Issue 6559, Pages 1104-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc1048
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Funding
- Melanoma Research Alliance
- NIH [R01CA229215]
- NIH Director's New Innovator Award [DP2CA186572]
- NIH Mentored Clinical Scientist Research Career Development Award [K08AR055368]
- Pershing Square Sohn Foundation
- Alan and Sandra Gerry Metastasis Research Initiative at the Memorial Sloan Kettering Cancer Center
- Harry J. Lloyd Foundation
- Consano
- Starr Cancer Consortium
- NYSTEM award [DOH01-STEM5-2016-00300]
- Starr Stem cell initiative
- Kirschstein-NRSA predoctoral fellowship [F31CA196305, F30CA220954, F30CA236442]
- Melanoma Research Foundation
- Medical Scientist Training Program [T32GM007739]
- NRSA [5F32MH116590-02]
- Frank Lappin Horsfall, Jr. Fellowship
- Molecular and Cell Biology Teaching Grant [T32GM008539]
- Individual Predoctoral to Postdoctoral Fellow Transition Award [5K00CA223016-04]
- Swiss National Science Foundation Postdoc.mobility fellowship [P2ZHP3_171967, P400PB_180672]
- NCI Core Facility Grant [P30 CA008748]
- Joanna M. Nicolay Melanoma Foundation Research Scholar Award
- Robert B. Catell Fellowship
- Swiss National Science Foundation (SNF) [P400PB_180672, P2ZHP3_171967] Funding Source: Swiss National Science Foundation (SNF)
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The intrinsic transcriptional program present in the cell of origin plays a key role in the transforming ability of oncogenes like BRAF(V600E), with developmental chromatin factors mediating oncogenic competence and allowing for proper response to oncogenes.
Oncogenes only transform cells under certain cellular contexts, a phenomenon called oncogenic competence. Using a combination of a human pluripotent stem cell-derived cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAF(V600E) along with additional mutations depends on the intrinsic transcriptional program present in the cell of origin. In both systems, melanocytes are less responsive to mutations, whereas both neural crest and melanoblast populations are readily transformed. Profiling reveals that progenitors have higher expression of chromatin-modifying enzymes such as ATAD2, a melanoma competence factor that forms a complex with SOX10 and allows for expression of downstream oncogenic and neural crest programs. These data suggest that oncogenic competence is mediated by regulation of developmental chromatin factors, which then allow for proper response to those oncogenes.
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