Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline

Keren Cheng; Yasunari Seita; Eoin C. Whelan; Ryo Yokomizo; Young Sun Hwang; Antonia Rotolo; Ian D. Krantz; Jill P. Ginsberg; Thomas F. Kolon; Priti Lal; Xunda Luo; Phillip M. Pierorazio; Rebecca L. Linn; Sandra Ryeom; Kotaro Sasaki

Cell Reports (Jun 2024)

Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline

Keren Cheng,
Yasunari Seita,
Eoin C. Whelan,
Ryo Yokomizo,
Young Sun Hwang,
Antonia Rotolo,
Ian D. Krantz,
Jill P. Ginsberg,
Thomas F. Kolon,
Priti Lal,
Xunda Luo,
Phillip M. Pierorazio,
Rebecca L. Linn,
Sandra Ryeom,
Kotaro Sasaki

Affiliations

Keren Cheng: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Yasunari Seita: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Eoin C. Whelan: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Ryo Yokomizo: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Young Sun Hwang: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Antonia Rotolo: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Ian D. Krantz: Division of Human Genetics, The Roberts Individualized Medical Genetics Center, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
Jill P. Ginsberg: Department of Pediatrics, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
Thomas F. Kolon: Division of Urology, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
Priti Lal: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA
Xunda Luo: Department of Pathology and Laboratory Medicine, University of Pennsylvania Presbyterian Medical Center, 51 North 39th Street, Philadelphia, PA 19104, USA
Phillip M. Pierorazio: Division of Urology, University of Pennsylvania Presbyterian Medical Center, 3737 Market St. 4th Floor, Philadelphia, PA 19104, USA
Rebecca L. Linn: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA; Department of Pathology, The Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA
Sandra Ryeom: Department of Surgery, Columbia University Irving Medical Center, 630 W. 168th Street, P&S 17-409, New York, NY 10032, USA
Kotaro Sasaki: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 6
p. 114323

Abstract

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Summary: Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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