Identifying the underlying molecular basis for such a transition would provide insight into the molecular pathogenesis of UM and yield a critical opportunity for early therapeutic intervention. Currently, it is not known whether high-risk and low-risk UMs are fundamentally distinct disease subtypes or whether genetic and/or epigenetic changes in a subpopulation of tumors cells can lead to evolution from a relatively indolent to an aggressive UM (Fig. A clinically-validated 12-gene signature-representative of the transcriptional changes that distinguish the two prognostic groups-is often used to identify patients with low-risk UM (Gene expression profile 1, GEP1) and high-risk tumors (Gene expression profile 2, GEP2) 18, 19 in the clinical setting. Third, they exhibit a distinctive gene expression signature 2, 17. Second, they are often monosomic for chromosome 3 2, 12, 13, and frequently harbor mutations in the BAP1 gene (located on chromosome 3) 2, 14-a component of the polycomb repressive deubiquitinase (PR-DUB) complex that hydrolyzes ubiquitin at lysine 119 of the repressive Histone 2A (H2AK119) 15, 16. First, they tend to have an “epithelioid” morphology with enlarged nuclei 10, 11.
Highly metastatic UM tumors differ from their more indolent counterparts in at least three ways 1, 3. Therefore, identifying patients at high-risk for metastasis and developing ways to intervene are critical priorities. Once metastases are detected, median survival is less than twelve months 4, 5, 6, 7, 8, 9. Uveal Melanoma (UM), a lethal eye cancer of adults and the second most common subtype of melanoma, is characterized by striking variability in metastatic tendency 1, 2, 3. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention. 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. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol.
This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. 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. 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.