肿瘤内异质性在癌症中很常见，特别是在未分化多形性肉瘤（UPS）等肉瘤中，其中单个细胞表现出高度的细胞源多样性。先前的研究表明，UPS 内的一小部分细胞（称为转移克隆 (MC)）负责转移。使用基于 CRISPR 的体内基因组筛选，我们确定了 COMPASS 复合体成员 Setd1a 是维持小鼠 UPS 中 MC 转移表型的关键调节因子。 Setd1a 的缺失抑制了 MC 的转移发展。转录组和染色质测序显示 UPS 中的 COMPASS 复杂靶基因（例如 Cxcl10）在 MC 中下调。删除非 MC 细胞中的 Cxcl10 会增加其转移潜力。用 COMPASS 复合物抑制剂治疗带有人类 UPS 异种移植物的小鼠，可以抑制转移，而不影响原发肿瘤的肿瘤生长。我们的数据确定了肉瘤细胞亚群中维持转移潜力的表观遗传程序。© 2024 作者。

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. Treating mice with human UPS xenografts with a COMPASS complex inhibitor suppressed metastasis without affecting tumor growth in the primary tumor. Our data identified an epigenetic program in a subpopulation of sarcoma cells that maintains metastatic potential.© 2024 The Author(s).