Reprogramming of Ovarian Granulosa Cells by YAP1 Leads to Development of High-Grade Cancer with Mesenchymal Lineage and Serous Features

Xiangmin Lv; Chunbo He; Cong Huang; Guohua Hua; Xingcheng Chen; Barbara K Timm; Victoria M Maclin; Abigail A Haggerty; Shelly K Aust; Denae M Golden; Bhavana J Dave; Yun-An Tseng; Li Chen; Hongbo Wang; Peichao Chen; David L Klinkebiel; Adam R Karpf; Jixin Dong; Ronny I Drapkin; Bo R Rueda; John S Davis; Cheng Wang

doi:10.1016/j.scib.2020.03.040

Reprogramming of Ovarian Granulosa Cells by YAP1 Leads to Development of High-Grade Cancer with Mesenchymal Lineage and Serous Features

Sci Bull (Beijing). 2020 Aug 15;65(15):1281-1296. doi: 10.1016/j.scib.2020.03.040. Epub 2020 Mar 30.

Authors

Xiangmin Lv^{1

2}, Chunbo He^{2

3}, Cong Huang¹, Guohua Hua^{1

3}, Xingcheng Chen^{4

5}, Barbara K Timm⁶, Victoria M Maclin⁶, Abigail A Haggerty⁷, Shelly K Aust⁷, Denae M Golden⁷, Bhavana J Dave⁷, Yun-An Tseng⁵, Li Chen^{1

8}, Hongbo Wang¹, Peichao Chen^{1

9}, David L Klinkebiel¹⁰, Adam R Karpf⁴, Jixin Dong⁴, Ronny I Drapkin¹¹, Bo R Rueda¹, John S Davis^{2

4}, Cheng Wang^{1

2}

Affiliations

¹ Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
² Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ College of Animal Sciences and Veterinary Medicine, Huazhong Agricultural University, Wuhan 47000, China.
⁴ Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁵ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁶ Heartland Center for Reproductive Medicine, Omaha, NE 68198, USA.
⁷ Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁸ Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
⁹ College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
¹⁰ Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
¹¹ Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

Understanding the cell-of-origin of ovarian high grade serous cancer (HGSC) is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological cancer. Recently, a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS studies. The cell-of-origin of this subtype of ovarian cancer is unknown. While pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology, we unexpectedly found that the Yes-associated protein 1 (YAP1), the major effector of the Hippo signaling pathway, induced dedifferentiation and reprogramming of the ovarian granulosa cells, a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity, leading to the development of high grade ovarian cancer with serous features. Our research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features.

Keywords: Mesenchymal type of high grade serous cancer; Ovarian granulosa cells; YAP1 oncogene; cell dedifferentiation; cell reprogramming; the Hippo pathway.

Abstract

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