STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Biniam Adane; Gabriela Alexe; Bo Kyung A Seong; Diana Lu; Elizabeth E Hwang; Denes Hnisz; Caleb A Lareau; Linda Ross; Shan Lin; Filemon S Dela Cruz; Melissa Richardson; Abraham S Weintraub; Sarah Wang; Amanda Balboni Iniguez; Neekesh V Dharia; Amy Saur Conway; Amanda L Robichaud; Benjamin Tanenbaum; John M Krill-Burger; Francisca Vazquez; Monica Schenone; Jason N Berman; Andrew L Kung; Steven A Carr; Martin J Aryee; Richard A Young; Brian D Crompton; Kimberly Stegmaier

doi:10.1016/j.ccell.2021.05.007

STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Cancer Cell. 2021 Jun 14;39(6):827-844.e10. doi: 10.1016/j.ccell.2021.05.007.

Authors

Biniam Adane¹, Gabriela Alexe², Bo Kyung A Seong¹, Diana Lu³, Elizabeth E Hwang³, Denes Hnisz⁴, Caleb A Lareau⁵, Linda Ross³, Shan Lin³, Filemon S Dela Cruz⁶, Melissa Richardson⁷, Abraham S Weintraub⁸, Sarah Wang³, Amanda Balboni Iniguez³, Neekesh V Dharia¹, Amy Saur Conway³, Amanda L Robichaud³, Benjamin Tanenbaum⁹, John M Krill-Burger⁹, Francisca Vazquez⁹, Monica Schenone⁹, Jason N Berman¹⁰, Andrew L Kung⁶, Steven A Carr⁹, Martin J Aryee¹¹, Richard A Young⁸, Brian D Crompton¹², Kimberly Stegmaier¹³

Affiliations

¹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Bioinformatics Graduate Program, Boston University, Boston, MA, USA.
³ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
⁵ Department of Pathology, Stanford University, Stanford, CA, USA.
⁶ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Department of Pathology, Dalhousie University, Halifax, NS, Canada.
⁸ Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Pediatrics and Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Charlestown, MA, USA.
¹² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: briand_crompton@dfci.harvard.edu.
¹³ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: kimberly_stegmaier@dfci.harvard.edu.

Abstract

The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.

Keywords: EWS/FLI1; Ewing sarcoma; POU3F2; PRC2; STAG1; STAG2; cohesin; fusion oncoprotein; metastasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bone Neoplasms / genetics*
Bone Neoplasms / pathology*
Cell Cycle Proteins / genetics*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Movement / genetics
Chromosomal Proteins, Non-Histone / metabolism
Cohesins
Enhancer Elements, Genetic
Female
Gene Expression Regulation, Neoplastic
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Mice
Mice, Inbred NOD
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oncogene Proteins, Fusion / genetics
POU Domain Factors / genetics
POU Domain Factors / metabolism
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism
Promoter Regions, Genetic
Proto-Oncogene Protein c-fli-1 / genetics
RNA-Binding Protein EWS / genetics
Sarcoma, Ewing / genetics*
Sarcoma, Ewing / pathology*
Xenograft Model Antitumor Assays
Zebrafish / genetics

Substances

Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
EWS-FLI fusion protein
Homeodomain Proteins
Nuclear Proteins
Oncogene Proteins, Fusion
POU Domain Factors
Proto-Oncogene Protein c-fli-1
RNA-Binding Protein EWS
STAG1 protein, human
STAG2 protein, human
transcription factor Brn-2
Polycomb Repressive Complex 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding