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Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma

Shuang Zhang, Tao Zhang, Igor Dolgalev, Hao Ran, Douglas A. Levine, Benjamin G. Neel
doi: https://doi.org/10.1101/481200
Shuang Zhang
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA
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  • For correspondence: Benjamin.Neel@nyumc.org Shuang.Zhang@nyumc.org
Tao Zhang
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA
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Igor Dolgalev
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA
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Hao Ran
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA
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Douglas A. Levine
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA
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Benjamin G. Neel
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, 10016, USA
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  • For correspondence: Benjamin.Neel@nyumc.org Shuang.Zhang@nyumc.org
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ABSTRACT

The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response.

SIGNIFICANCE The cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 29, 2018.
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Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma
Shuang Zhang, Tao Zhang, Igor Dolgalev, Hao Ran, Douglas A. Levine, Benjamin G. Neel
bioRxiv 481200; doi: https://doi.org/10.1101/481200
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Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma
Shuang Zhang, Tao Zhang, Igor Dolgalev, Hao Ran, Douglas A. Levine, Benjamin G. Neel
bioRxiv 481200; doi: https://doi.org/10.1101/481200

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