biostudies-literatureBan GINational Cancer InstituteNCI NIH HHSNIAMS NIH HHSNIH110187https://www.ebi.ac.uk/biostudies/studies/S-EPMC11233968biostudies-literatureUnknown27(7)Intratumoral heterogeneity is common in cancer, particularly in sarcomas like undifferentiated pleomorphic sarcoma (UPS), where individual cells demonstrate a high degree of cytogenic diversity. Previous studies showed that a small subset of cells within UPS, known as the metastatic clone (MC), as responsible for metastasis. Using a CRISPR-based genomic screen in-vivo, we identified the COMPASS complex member Setd1a as a key regulator maintaining the metastatic phenotype of the MC in murine UPS. Depletion of Setd1a inhibited metastasis development in the MC. Transcriptome and chromatin sequencing revealed COMPASS complex target genes in UPS, such as Cxcl10, downregulated in the MC. Deleting Cxcl10 in non-MC cells increased their metastatic potential. TreaiScienceThe COMPASS complex maintains the metastatic capacity imparted by a subpopulation of cells in UPS.PMC11233968R35 CA197616R00 AR077685R01 CA183811R01 CA2514072R35 CA197616Nakagawa MBrowne MAlman BANadesan PIshikawa KGuardino NTang JKirsch DGDiao YShimada EOu JMartin JTPuviindran VXiang YBan GIWallace AfalseThe COMPASS complex maintains the metastatic capacity imparted by a subpopulation of cells in UPS.Intratumoral heterogeneity is common in cancer, particularly in sarcomas like undifferentiated pleomorphic sarcoma (UPS), where individual cells demonstrate a high degree of cytogenic diversity. Previous studies showed that a small subset of cells within UPS, known as the metastatic clone (MC), as responsible for metastasis. Using a CRISPR-based genomic screen in-vivo, we identified the COMPASS complex member Setd1a as a key regulator maintaining the metastatic phenotype of the MC in murine UPS. Depletion of Setd1a inhibited metastasis development in the MC. Transcriptome and chromatin sequencing revealed COMPASS complex target genes in UPS, such as Cxcl10, downregulated in the MC. Deleting Cxcl10 in non-MC cells increased their metastatic potential. Trea2024-01-01T00:00:00Z2024 Jul2026-06-01T07:03:28.078Z2024-11-09T15:17:09.164ZS-EPMC112339683898945110.1016/j.isci.2024.110187