期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25529-z
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资金
- Melanoma Research Alliance
- Burroughs Wellcome Fund
- Fund for Ophthalmic Knowledge
- National Cancer Institute [R01CA256188-01]
- Office Of The Director, National Institutes of Health [DP5OD026395]
- Department of Defense Breast Cancer Research Breakthrough Award [W81XWH- 16-1-0315, BC151244]
- Parker Institute for Immunotherapy at MSKCC
- Josie Robertson Foundation
- MSKCC core grant [P30-CA008748]
- Defeat GBM Program of the National Brain Tumor Society
- NVIDIA Foundation
- Compute for the Cure
- Ben and Catherine Ivy Foundation
- National Institutes of Health [NS 73831]
Researchers found that the progression of uveal melanoma is driven by the loss of Polycomb Repressive Complex 1, leading to chromosomal instability, inflammatory signaling, and migration.
Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention. The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.
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