Volume 252, Issue 2 p. 201-214
Original Paper

Single cell transcriptomes of normal endometrial derived organoids uncover novel cell type markers and cryptic differentiation of primary tumours

Dawn R Cochrane

Dawn R Cochrane

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

These authors contributed equally.

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Kieran R Campbell

Kieran R Campbell

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

These authors contributed equally.

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Kendall Greening

Kendall Greening

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

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Germain C Ho

Germain C Ho

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

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James Hopkins

James Hopkins

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Minh Bui

Minh Bui

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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J Maxwell Douglas

J Maxwell Douglas

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Vassilena Sharlandjieva

Vassilena Sharlandjieva

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Aslı D Munzur

Aslı D Munzur

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Daniel Lai

Daniel Lai

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Maya DeGrood

Maya DeGrood

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

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Evan W Gibbard

Evan W Gibbard

Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

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Samuel Leung

Samuel Leung

Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Niki Boyd

Niki Boyd

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Angela S Cheng

Angela S Cheng

Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Christine Chow

Christine Chow

Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada

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Jamie LP Lim

Jamie LP Lim

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

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David A Farnell

David A Farnell

Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, BC, Canada

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Stefan Kommoss

Stefan Kommoss

Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany

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Friedrich Kommoss

Friedrich Kommoss

Institute of Pathology, Medizin Campus Bodensee, Friedrichshafen, Germany

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Andrew Roth

Andrew Roth

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

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Lien Hoang

Lien Hoang

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

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Jessica N McAlpine

Jessica N McAlpine

Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, BC, Canada

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Sohrab P Shah

Sohrab P Shah

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

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David G Huntsman

Corresponding Author

David G Huntsman

Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada

Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

Correspondence to:

DG Huntsman, Department of Molecular Oncology, BC Cancer Agency, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada.

E-mail: [email protected]

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First published: 19 July 2020
Citations: 32
DGH is an Associate Editor of The Journal of Pathology. No other conflicts of interests were declared.

Abstract

Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of secretory cells (MPST) and several markers of ciliated cells (FAM92B, WDR16, and DYDC2) were validated by immunohistochemistry on organoids and tissue sections. We performed single cell sequencing on endometrial and ovarian tumours and found both secretory-like and ciliated-like tumour cells. We found that ciliated cell markers (DYDC2, CTH, FOXJ1, and p73) and the secretory cell marker MPST were expressed in endometrial tumours and positively correlated with disease-specific and overall survival of endometrial cancer patients. These findings suggest that expression of differentiation markers in tumours correlates with less aggressive disease, as would be expected for tumours that retain differentiation capacity, albeit cryptic in the case of ciliated cells. These markers could be used to improve the risk stratification of endometrial cancer patients, thereby improving their management. We further assessed whether consideration of MPST expression could refine the ProMiSE molecular classification system for endometrial tumours. We found that higher expression levels of MPST could be used to refine stratification of three of the four ProMiSE molecular subgroups, and that any level of MPST expression was able to significantly refine risk stratification of the copy number high subgroup which has the worst prognosis. Taken together, this shows that single cell sequencing of putative cells of origin has the potential to uncover novel biomarkers that could be used to guide management of cancers. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Data availability statement

The single cell data (raw Fastq files) have been uploaded to the European Genome-Phenome archive with a study accession number of EGAS00001004466 and can be found at https://ega-archive.org/studies/EGAS00001004466. The processed matrix files can be found at https://zenodo.org/record/3937811.