A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Kate Lawrenson; Marcos A.S. Fonseca; Annie Y. Liu; Felipe Segato Dezem; Janet M. Lee; Xianzhi Lin; Rosario I. Corona; Forough Abbasi; Kevin C. Vavra; Huy Q. Dinh; Navjot Kaur Gill; Ji-Heui Seo; Simon Coetzee; Yvonne G. Lin; Tanja Pejovic; Paulette Mhawech-Fauceglia; Amy C. Rowat; Ronny Drapkin; Beth Y. Karlan; Dennis J. Hazelett; Matthew L. Freedman; Simon A. Gayther; Houtan Noushmehr

Cell Reports (Dec 2019)

A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Kate Lawrenson,
Marcos A.S. Fonseca,
Annie Y. Liu,
Felipe Segato Dezem,
Janet M. Lee,
Xianzhi Lin,
Rosario I. Corona,
Forough Abbasi,
Kevin C. Vavra,
Huy Q. Dinh,
Navjot Kaur Gill,
Ji-Heui Seo,
Simon Coetzee,
Yvonne G. Lin,
Tanja Pejovic,
Paulette Mhawech-Fauceglia,
Amy C. Rowat,
Ronny Drapkin,
Beth Y. Karlan,
Dennis J. Hazelett,
Matthew L. Freedman,
Simon A. Gayther,
Houtan Noushmehr

Affiliations

Kate Lawrenson: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Corresponding author
Marcos A.S. Fonseca: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Annie Y. Liu: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Felipe Segato Dezem: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Janet M. Lee: Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Xianzhi Lin: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Rosario I. Corona: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Forough Abbasi: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Kevin C. Vavra: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Huy Q. Dinh: Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA
Navjot Kaur Gill: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
Ji-Heui Seo: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Simon Coetzee: Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Yvonne G. Lin: Division of Gynecologic Oncology, Department of Obstetrics-Gynecology, University of Southern California/Keck School of Medicine, Los Angeles, Los Angeles, CA, USA
Tanja Pejovic: Division of Gynecologic Oncology, Department of Obstetrics-Gynecology, University of Southern California/Keck School of Medicine, Los Angeles, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
Paulette Mhawech-Fauceglia: Aurora Diagnostics, Austin, TX, USA
Amy C. Rowat: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA
Ronny Drapkin: Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
Beth Y. Karlan: Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Dennis J. Hazelett: Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Matthew L. Freedman: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Simon A. Gayther: Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Corresponding author
Houtan Noushmehr: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; Corresponding author

Journal volume & issue: Vol. 29, no. 11
pp. 3726 – 3735.e4

Abstract

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Summary: Fallopian tube secretory epithelial cells (FTSECs) are likely the main precursor cell type of high-grade serous ovarian cancers (HGSOCs), but these tumors may also arise from ovarian surface epithelial cells (OSECs). We profiled global landscapes of gene expression and active chromatin to characterize molecular similarities between OSECs (n = 114), FTSECs (n = 74), and HGSOCs (n = 394). A one-class machine learning algorithm predicts that most HGSOCs derive from FTSECs, with particularly high FTSEC scores in mesenchymal-type HGSOCs (padj < 8 × 10−4). However, a subset of HGSOCs likely derive from OSECs, particularly HGSOCs of the proliferative type (padj < 2 × 10−4), suggesting a dualistic model for HGSOC origins. Super-enhancer (SE) landscapes were also more similar between FTSECs and HGSOCs than between OSECs and HGSOCs (p < 2.2 × 10−16). The SOX18 transcription factor (TF) coincided with a HGSOC-specific SE, and ectopic overexpression of SOX18 in FTSECs caused epithelial-to-mesenchymal transition, indicating that SOX18 plays a role in establishing the mesenchymal signature of fallopian-derived HGSOCs. : Lawrenson et al. profile gene expression and active chromatin in ∼200 ovarian and fallopian epithelial isolates and implement machine learning to demonstrate that most high-grade serous ovarian cancers (HGSOCs) derive from fallopian tube epithelial cells, but a subset may originate from ovarian epithelia. SOX18 induces mesenchymal features to drive early neoplasia in fallopian tube precursors. Keywords: high-grade serous ovarian cancer, ovarian surface epithelial cell, fallopian tube secretory epithelial cell, super enhancers, transcription factors, SOX18, single-cell RNA-seq, RNA-seq, machine learning, one-class logistic regression models, dual origins

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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