The COMPASS complex maintains the metastatic capacity imparted by a subpopulation of cells in UPS
Ga I. Ban,
Vijitha Puviindran,
Yu Xiang,
Puvi Nadesan,
Jackie Tang,
Jianhong Ou,
Nicholas Guardino,
Makoto Nakagawa,
MaKenna Browne,
Asjah Wallace,
Koji Ishikawa,
Eijiro Shimada,
John T. Martin,
Yarui Diao,
David G. Kirsch,
Benjamin A. Alman
Affiliations
Ga I. Ban
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Vijitha Puviindran
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Yu Xiang
Department of Cell Biology and Duke Regeneration Center, Duke University School of Medicine, Durham, NC, USA
Puvi Nadesan
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Jackie Tang
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Jianhong Ou
Department of Cell Biology and Duke Regeneration Center, Duke University School of Medicine, Durham, NC, USA
Nicholas Guardino
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Makoto Nakagawa
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
MaKenna Browne
Department of Cell Biology and Duke Regeneration Center, Duke University School of Medicine, Durham, NC, USA
Asjah Wallace
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Koji Ishikawa
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Eijiro Shimada
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
John T. Martin
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA
Yarui Diao
Department of Cell Biology and Duke Regeneration Center, Duke University School of Medicine, Durham, NC, USA
David G. Kirsch
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA; The Princes Margaret Cancer Centre, Department of Radiation Oncology, University Health Network and the University of Toronto, Toronto, ON, Canada
Benjamin A. Alman
Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA; Corresponding author
Summary: 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.
