Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression

Mathieu F. Bakhoum (), Jasmine H. Francis, Albert Agustinus, Ethan M. Earlie, Melody Di Bona, David H. Abramson, Mercedes Duran, Ignas Masilionis, Elsa Molina, Alexander N. Shoushtari, Michael H. Goldbaum, Paul S. Mischel (), Samuel F. Bakhoum () and Ashley M. Laughney ()
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Mathieu F. Bakhoum: Yale University School of Medicine
Jasmine H. Francis: Memorial Sloan Kettering Cancer Center
Albert Agustinus: Memorial Sloan Kettering Cancer Center
Ethan M. Earlie: Weill Cornell Medicine
Melody Di Bona: Memorial Sloan Kettering Cancer Center
David H. Abramson: Memorial Sloan Kettering Cancer Center
Mercedes Duran: Memorial Sloan Kettering Cancer Center
Ignas Masilionis: Memorial Sloan Kettering Cancer Center
Elsa Molina: University of California San Diego
Alexander N. Shoushtari: Memorial Sloan Kettering Cancer Center
Michael H. Goldbaum: University of California San Diego
Paul S. Mischel: Stanford University School of Medicine
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Ashley M. Laughney: Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25529-z

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