The world of medicine has made remarkable strides in diagnosing and treating various health conditions, but when it comes to many women’s health issues, progress is lacking.
Vincent Center for Reproductive Biology
Wang Lab: Cheng Wang, PhD
Explore This Lab
Globally, around 860,000 women are expected to be diagnosed with ovarian or cervical cancers each year, with an estimated 490,000 associated deaths worldwide. These stunning numbers are attributed, in part, to the fact that the etiology of these cancers remains unclear. Research in my laboratory mainly focuses on identifying the signaling pathways and molecules that contribute to the physiological and pathological changes in the female reproductive tract (mainly ovarian, fallopian tube, and cervical tissues), aiming to provide new strategies for effective prevention, early diagnosis and better treatment of these lethal gynecological malignancies. Currently, we are investigating the role of the Hippo/YAP signaling pathway in the physiology and pathogenesis of organs in the female reproductive tract.
Defining the functional significance of the Hippo/YAP signaling pathway in the initiation and progression of high-grade serious ovarian cancer (HGSC)
Ovarian cancer is the most lethal gynecological cancer in women in Western countries. Despite the rapid progress that has been made in ovarian cancer research in the past decades, the mortality rate of epithelial ovarian cancer has not been significantly changed. The ovarian cancer research project in my laboratory aims to uncover the molecular mechanisms by which environmental pathogens interact with the intrinsic genetic/genomic alterations in the fallopian tube and ovarian tissues to drive the development of high-grade serous ovarian cancer. Our previous studies had identified the disrupted Hippo/YAP signaling pathway as a critical contributor to HGSC development (Endocrine-Related Cancer, 2014; Oncogene, 2015, 2016; EMBO Rep, 2019, Sci Bull, 2020).
Currently, we are investigating the cellular and molecular mechanisms by which the sexually-transmitted pathogens interact with the Hippo/YAP signaling pathway to drive the malignant transformation of ovarian and fallopian tube epithelial cells using transgenic animal models. We expect that research results derived from this project will put new insight into our understanding of HGSC etiology and provide new clues to improve the current prevention and treatment of HGSC. This project is supported by NIH, Collen’s dream foundation, Rivkin Center for Ovarian Cancer Research, the Ruggles family foundation, and VCRB/MGH research funds.
Delineating the role of the Hippo pathway in the paracrine/autocrine regulation of ovarian function
The improvement in cancer diagnosis and treatment over the last decades has resulted in a significant increase in the cancer survival rate. The American Cancer Society (ACS) estimated that more than 410,000 young female cancer survivors (≤ 39 years old) live in the United States. Although cancer treatment saves the lives of young female cancer patients, it frequently damages their ovarian function, resulting in subfertility and infertility. A decrease in or loss of fertility is also a traumatic issue that significantly impacts the long-term quality of life. There is an urgent need to develop strategies to preserve fertility and improve the life quality of these young female cancer survivors.
Our recent studies, including results derived from the recently developed GC-specific Yap1 gene knockout mouse model (GC-YapKO) (FASEB J, 2019; Biol Reprod, 2019), indicated that the Hippo/YAP signaling pathway plays a critical role in determining granulosa cell fate and follicle development. Based on these findings, we are currently testing the hypothesis that targeting the Hippo signaling pathway has the potential to facilitate the preservation of ovarian function and female fertility. We expect to discover the novel Hippo pathway-based drugs to conserve ovarian function and preserve the fertility of young female cancer patients. This project was initially established with the support from the NIH Pathway to Independence Award (k99/R00) and is currently supported by the VCRB/MGH research funds.
Demonstrating how the Hippo-Yap signaling pathway interacts with high-risk HPV oncoproteins to regulate cervical epithelial cell overgrowth and malignant transformation.
Cervical cancer is the fourth leading cause of cancer death in women. Since more than 95% of cervical cancer (CVC) patients are positive for human papillomavirus (HPV) DNA, it is widely accepted that all cases of CVC are caused by high-risk HPV (hrHPV). However, accumulating evidence indicates that hrHPV alone is insufficient to induce cervical carcinogenesis. Unknown factors unique to an individual’s genetics/genomic background may play a critical role in CVC development. The molecular mechanisms underlying cervical tumorigenesis remain unclear. Research results in my laboratory showed that YAP1, the major effector of the Hippo tumor-suppressive pathway, interacts with hrHPV to drive cervical epithelial cell transformation and promote CVC development (EMBO Molecular Medicine, 2015).
Under the support from NIH, we generated a unique transgenic mouse model which shows that hyperactivation of YAP1 can initiate invasive CVC in the absence of hrHPV (Cell Reports, 2019). These findings challenge the HPV dogma of cervical cancer development. Our more recent mechanistic studies demonstrated that YAP1 and LATS2(the upstream suppressor of YAP1 oncogene) form a negative feedback loop to maintain tissue homeostasis (EMBO reports, 2019). The disruption of this YAP1-LATS2 loop would block YAP1-induced senescence, leading to the malignant transformation of YAP1-hyperactivated cells. The ongoing studies in my lab are focused on translating our novel findings from laboratory bench to bedside. This project is supported by NIH, the Ruggles family foundation, and VCRB/MGH funds.
Who We Are
Meet Our Team
Cheng Wang, PhD
Investigator, Vincent Center for Reproductive Biology
Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School
Postdoctoral Research Fellows:
- Xiangmin Lv, PhD
- Cong Huang, PhD
- Hongbo Wang, PhD
Li Chen, Graduate Research Assistant
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.
Lv X, He C, Huang C, Wang H, Hua G, Wang Z, Zhou J, Chen X, Ma B, Timm BK, Maclin V, Dong J, Rueda BR, Davis JS, Wang C. Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development. FASEB J. 2019, 33(9):10049-10064. doi: 10.1096/fj.201900179RR.
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.
Plewes MR, Hou X, Zhang P, Liang A, Hua G, Wood JR, Cupp AS, Lv X, Wang C, Davis JS. Yes-associated protein (YAP1) is required for proliferation and function of bovine granulosa cells in vitro. Biol Reprod. 2019, pii: ioz139. doi: 10.1093/biolre/ioz139
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, 16(6):1080-1091. doi: 10.1158/1535-7163.MCT-16-0626.
Wang F, Xu C, Reece EA, Li X, Wu Y, Harman C, Yu J, Dong D, Wang C, Yang P, Zhong J, Yang P. Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy. Nat Commun. 2017, 8:15182. doi: 10.1038/ncomms15182.
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.
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.
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.
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.
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. (Cover article)
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