Wang Lab: Cheng Wang, PhD

Overview

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.

Current Projects

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

Principal Investigator

Cheng Wang, PhD
Investigator, Vincent Center for Reproductive Biology
Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

Postdoctoral Research Fellows

Jiyuan Liu, PhD

Jiyuan is a biomedical researcher with combined expertise in bench work and bioinformatics. He was trained in basic and translational biomedical research and earned his PhD in nutrition science from China Agricultural University (CAU) in 2018. He was also trained and excelled in mathematic modeling and programming for machine learning and represented CAU to compete in the National Mathematical Contest in Modelling. Supported by a joint program, he received research training in nutrition and immunology at the University of Wisconsin-Madison during his graduate study. Currently, he works as a Research Fellow in Wang Laboratory at MGH to study the etiology of carcinomas developed from the female reproductive tract and the subfertility/infertility associated with cancer treatment using genetically-modified animal models and customized in-depth (single-cell and spatial) transcriptomics. He is pursuing the establishment of an independent cancer-prevention research laboratory in the near future.

Laboratory Staff

Jinpeng Ruan
Research Assistant

Jinpeng is a PhD candidate at Xiamen University. He received his bachelor’s degree in biological sciences from Xiamen University. He now works as a graduate research assistant at Wang Lab. His Ph.D. research project focuses on the cellular and molecular mechanisms by which environmental pollutants induce polycystic ovary syndrome (PCOS). His current research focuses on developing new strategies to improve the prevention, diagnosis, and treatment of high-grade serous ovarian carcinoma.

Xingeng (Vincent) Zhao, MS
Research Technician II

Vincent earned his Bachelor of Science from the University of Waterloo joint with Beijing Jiaotong University in 2022. He studied physics and biophysics including electron energy levels and molecular orbital hybridization during his undergraduate training. He then attended Columbia University to study genetics in Tosches Lab and Firestein lab, and later obtained his master’s degree in 2024. In MGH, his current research focuses on exploring cellular and molecular mechanisms underlying high-grade serous ovarian cancer development using spatial transcriptomics.

Students

• Madelyn Leigh Moness
• Isabelle Montoute

Publications