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Research at Mass General
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1. Defining the functional significance of the Hippo/YAP signaling pathway in the initiation and/or progression of the fallopian tube secretory epithelial cell (FTSEC)-derived ovarian high-grade serious carcinoma (HGSC)
Our goal is to explore roles of the Hippo/YAP signaling pathway in the initiation and progression of ovarian high-grade serious carcinoma (HGSC) with a FTSEC origin. These proposed studies are expected to answer the following questions:
Achievement of this proposed project will provide new insight into our understanding on the development and progression of ovarian HGSC and could open a new window for the prevention and therapy of ovarian cancer.
With the help from many collaborators, we have established several important transgenic mouse strains to develop the fallopian tube-specific and ovary-specific MST1/2 knockout and YAP knockin mouse models. These are powerful tools for studying the role of the Hippo pathway in ovarian HGSC.
The basic functional unit of the ovary is the follicle. Narrowly regulated cell-cell communication plays critical role in the follicle cell proliferation, differentiation, steroidogenesis, oocyte maturation and ovulation.
Our previous findings suggested ovarian follicle development is not only controlled by the hypothalamus-pituitary-gonad axis, but also tightly regulated by local growth factors, hormones, and cell adhesion molecules.
In particular, our previous study unveiled the role of GPR30 (now call GPER1), the membrane G protein-coupled estrogen receptor, in mediating the estrogen action during ovarian cell-cell communication and follicle development. These findings bolstered our understanding on the mechanisms underlying the endocrine, paracrine and autocrine regulation of ovarian physiology.
It is our hope that providing a better understanding of the key signaling pathways in the ovary will aid in the pursuit of overcoming infertility which impacts a significant number of women.
3. Demonstrating how the Hippo-Yap signaling pathway, interacts with high-risk HPV oncoproteins to regulate cervical epithelial cell transformation and cervical cancer cell proliferation.
Cervical cancer is the fourth leading cause of cancer death in women. Although high risk human HPVs are thought to be the cause of cervical cancer, convincing evidence indicates that HPV alone is insufficient to induce cervical carcinogenesis.
The molecular mechanisms underlying cervical tumorigenesis are unclear. Our recent preliminary studies showed that YAP, the major effector of the Hippo tumor suppressive pathway, interacts with high-risk HPV oncoproteins to regulate cervical epithelial cell transformation and cervical cancer cell proliferation.
Based on these novel findings, we hypothesize that the Hippo pathway interacts with the high-risk HPV to drive the initiation and progression of cervical cancer.
Our proposed studies are designed to uncover the pathological role of the interaction between the high-risk HPV oncoproteins and the Hippo/YAP pathway and to unveil the molecular mechanisms underlying the observed crosstalk.
Cheng Wang, PhDAssociate Investigator, Vincent Center for Reproductive BiologyMember of the Faculty of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School
Li Chen, Graduate Research Assistant
Complete list of published work in MyBibliography
He C, Lv X, Huang C, Angeletti PC, Hua G, Dong J, Zhou J, Wang Z, Ma B, Chen X, Lambert PF, Rueda BR, Davis JS, Wang C. A Human Papillomavirus-Independent Cervical Cancer Animal Model Reveals Unconventional Mechanisms of Cervical Carcinogenesis. Cell Rep. 2019, 26(10):2636-2650.e5. doi: 10.1016/j.celrep.2019.02.004.
He C, Lv X, Huang C, Hua G, Ma B, Chen X, Angeletti PC, Dong J, Zhou J, Wang Z, Rueda BR, Davis JS, Wang C. YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis. EMBO Rep. 2019 Mar;20(3). pii: e44948. doi: 10.15252/embr.201744948.
Wang F, Xu C, Reece EA, Li X, Wu Y, Harman C, Yu J, Dong D, Wang C, Yang P, Zhong J, and Yang P. Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy. Nat Commun. 2017. (Accepted March 3, 2017)
Lv X, He C, Huang C, Hua G, Wang Z, Remmenga SW, Rodabough KJ, Karpf, AR, Dong J, Davis JS, Wang C. G-1 inhibits breast cancer cell growth via targeting colchicine-binding site of tubulin to interfere with microtubule assembly. Mol Cancer Ther. 2017, [Epub ahead of print]. NIHMS854637. Doi: 10.1158/1535-7163.MCT-16-0626
Hua G, Lv X, He C, Remmenga SW, Rodabough KJ, Dong J, Yang L, Lele SM, Yang P, Zhou J, Karst A, Drapkin RI, Davis JS and Wang C. YAP induces high-grade serous carcinoma in fallopian tube secretory epithelial cells. Oncogene, 2016, 35(17): 2247 - 2265. (Corresponding author)
Guohua Hua, Chunbo He, Xiangmin Lv, Lin Fan, Chen Wang, Steven W. Remmenga, Kerry J. Rodabaugh, Liguo Yang, Subodh M. Lele, Peixin Yang, Adam Karpf, John S. Davis, Wang C. The Four and a Half LIM Domains 2 (FHL2) Regulates Ovarian Granulosa Cell Tumor Progression via Controlling AKT1 Transcription. Cell death & Dis. 2016, 7:e2297. Doi: 10.1038/cddis.2016.207
He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, Dong J, Remmenga SW, Rodabough KJ, Zhou J, Lambert PF, Yang P, Davis JS, Wang C. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med. 2015, 7: 1426-1449. (Corresponding author)
He C, Lv X, Hua GH, Lele SM, Remmenga S, Dong J, Davis JS, Wang C. YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression. Oncogene, 2015, 34:6040-6054. (Corresponding author)
Jiang C, Hou XY, Wang C, May JV, Butnev VY, Bousfield GR, Davis JS. Hypo-glycosylated hFSH has greater bioactivity than fully-glycosylated recombinant hFSH in human granulosa cells. J Clin Endocrinol Metab. 2015, 100: E852-860
Wu Y, Wang F, Fu M, Wang C, Ouon MJ, Yang P.
David Fu, Xiangmin Lv, Guohua Hua, Chunbo He, Jixin Dong, Subodh M Lele, David Wan-Cheng Li, Qiongli Zhai, John S Davis, and Wang C. YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors. Endocr Relat Cancer. 2014, 21(2):297-310. (Corresponding author) (Cover article)
Lv X, Wang C. G-1: new potential therapeutic option for ovarian cancer. Cancer Cell & Microenvironment. 2014, 1:10-13. (Corresponding author)
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