摘要
高级别浆液性卵巢癌(HGSC)是临床中最常见、且恶性程度最高的卵巢癌.深入了解高级别浆液性卵巢癌的起源细胞可对该亚型卵巢癌进行有效预防和早期诊断.最近TCGA和AOCS通过分子分型研究发现了一种具有间充质特征的高级别浆液性卵巢癌亚型,并且表明该亚型是所有新发现的亚型中预后最差的一种,而且目前大家对于这种卵巢癌新亚型的起源细胞一无所知.在研究Hippo信号通路在卵巢颗粒细胞生理和病理中的作用时,意外地发现Hippo信号传导途径的主要效应分子YAP1的高度激活可以诱导具有间质谱系和高可塑性的卵巢颗粒细胞的去分化与重编程,最终导致具有浆液性特征的高级别卵巢癌的发生.本文的研究结果揭示了具间质特征的高级别浆液性卵巢癌的一种潜在起源细胞.
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.
作者
吕向民
何春波
黄聪
滑国华
陈骍程
Barbara K.Timm
Victoria M.Maclin
Abigail A.Haggerty
Shelly K.Aust
Denae M.Golden
Bhavana J.Dave
Yun-An Tseng
陈利
王洪波
陈培超
David L.Klinkebiel
Adam R.Karpf
Jixin Dong
Ronny I.Drapkin
Bo R.Rueda
John S.Davis
王诚
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(Vincent Center for Reproductive Biology,Department of Obstetrics and Gynecology,Massachusetts General Hospital,Harvard Medical School,Boston,MA 02114,USA;Olson Center for Women's Health,Department of Obstetrics and Gynecology,University of Nebraska Medical Center,Omaha,NE 68198,USA;College of Animal Sciences and Veterinary Medicine,Huazhong Agricultural University,Wuhan 470000,China;Fred&Pamela Buffett Cancer Center,University of Nebraska Medical Center,Omaha,NE 68198,USA;Department of Pathology and Microbiology.University of Nebraska Medical Center,Omaha,NE 68198,USA;Heartland Center for Reproductive Medicine,Omaha,NE 68198,USA;Munroe-Meyer Institute,University of Nebraska Medical Center,Omaha,NE 68198,USA;Key Laboratory of Animal Ecology and Conservation Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China;College of Life and Environmental Science,Wenzhou University,Wenzhou 325035,China;Biochemistry and Molecular Biology,University of Nebraska Medical Center,Omaha,NE 68198,USA;Department of Obstetrics and Gynecology,University of Pennsylvania,Philadelphia,PA 19104,USA)
基金
supported by the National Cancer Institute/the National Institute of Health(1R01CA197976,1R01CA201500)
Vincent Memorial Hospital Foundation
the Vincent Center for Reproductive Biology
the Olson Center for Women’s Health
University of Nebraska Medical Center Graduate Studies Fellowship
the Fred&Pamela Buffett Cancer Center(LB595)
Colleen’s Dream Foundation
Marsha Rivkin Center for Ovarian Cancer Research(the Barbara Learned Bridge Funding Award)
the Co BRE grant from the Nebraska Center for Cellular Signaling/the National Institute of General Medical Science/the National Institute of Health(5P30GM106397)。
关键词
卵巢颗粒细胞
恶性程度
重编程
信号传导途径
卵巢癌
浆液性
效应分子
早期诊断
Ovarian granulosa cells
Cell reprogramming
Cell dedifferentiation
The Hippo pathway
YAP1 oncogene
Mesenchymal type of high grade serous
cancer
