Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1
Qu Deng,
Ramakrishnan Natesan,
Florencia Cidre-Aranaz,
Shehbeel Arif,
Ying Liu,
Reyaz ur Rasool,
Pei Wang,
Erick Mitchell-Velasquez,
Chandan Kanta Das,
Endrit Vinca,
Zvi Cramer,
Patrick J. Grohar,
Margaret Chou,
Chandan Kumar-Sinha,
Kristy Weber,
T.S. Karin Eisinger-Mathason,
Nicolas Grillet,
Thomas Grünewald,
Irfan A. Asangani
Affiliations
Qu Deng
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Ramakrishnan Natesan
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Florencia Cidre-Aranaz
Max-Eder Research Group of Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany; Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany
Shehbeel Arif
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Ying Liu
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, BRBII/III, Philadelphia, PA, USA
Reyaz ur Rasool
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Pei Wang
Department of Otolaryngology-Head & Neck Surgery, School of Medicine, Stanford University, Stanford, CA, USA
Erick Mitchell-Velasquez
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Chandan Kanta Das
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Endrit Vinca
Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Hopp Children’s Cancer Center (KiTZ), Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Zvi Cramer
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA
Patrick J. Grohar
Children's Hospital of Philadelphia, Philadelphia, PA, USA
Margaret Chou
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, BRBII/III, Philadelphia, PA, USA
Chandan Kumar-Sinha
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
Kristy Weber
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
T.S. Karin Eisinger-Mathason
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, BRBII/III, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Nicolas Grillet
Department of Otolaryngology-Head & Neck Surgery, School of Medicine, Stanford University, Stanford, CA, USA
Thomas Grünewald
Max-Eder Research Group of Pediatric Sarcoma Biology, Institute of Pathology, LMU Munich, Munich, Germany; Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Hopp Children’s Cancer Center (KiTZ), Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
Irfan A. Asangani
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Summary: Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic transcription program through de novo enhancers. By integrative analysis of thousands of transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, and normal tissues, we identify a 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) that stratifies EwS from pan-cancer. Among the ESS32, LOXHD1, encoding a stereociliary protein, is the most highly expressed gene through an alternative transcription start site. Deletion or silencing of EWSR1::FLI1 bound upstream de novo enhancer results in loss of the LOXHD1 short isoform, altering EWSR1::FLI1 and HIF1α pathway genes and resulting in decreased proliferation/invasion of EwS cells. These observations implicate LOXHD1 as a biomarker and a determinant of EwS metastasis and suggest new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.
