title: An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis.
abstract: Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers, with diagnosis often at a late stage. Metastasis is a major cause of death in patients with EOC, but the underlying molecular mechanisms remain obscure. Here, we utilized an integrated approach to find potential key transcription factors involved in ovarian cancer metastasis and identified STAT4 as a critical player in ovarian cancer metastasis. We found that activated STAT4 was overexpressed in epithelial cells of ovarian cancer and STAT4 overexpression was associated with poor outcome of ovarian cancer patients, which promoted metastasis of ovarian cancer in both in vivo and in vitro. Although STAT4 mediated EOC metastasis via inducing epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells in vivo, STAT4 failed to induce EMT directly in vitro, suggesting that STAT4 might mediate EMT process via cancer-stroma interactions. Further functional analysis revealed that STAT4 overexpression induced normal omental fibroblasts and adipose- and bone marrow-derived mesenchymal stem cells to obtain cancer-associated fibroblasts (CAF)-like features via induction of tumor-derived Wnt7a. Reciprocally, increased production of CAF-induced CXCL12, IL6 and VEGFA within tumor microenvironment could enable peritoneal metastasis of ovarian cancer via induction of EMT program. In summary, our study established a model that STAT4 promotes ovarian cancer metastasis via tumor-derived Wnt7a-induced activation of CAFs.
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: G
authors.initials: G
authors.lastname: Ji
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: X
authors.initials: X
authors.lastname: Le
authors.affiliation: College of Biological Sciences, Sichuan University, Chengdu, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.affiliation: College of Biological Sciences, Sichuan University, Chengdu, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology, West China Second Hospital, Sichuan University, Chengdu, China.
authors.forename: M
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Pathology, West China Second Hospital, Sichuan University, Chengdu, China.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: W B
authors.initials: WB
authors.lastname: Lau
authors.affiliation: Department of Surgery, Emergency Medicine, Kaiser Santa Clara Medical Center, Affiliate of Stanford University, Santa Clara, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Lau
authors.affiliation: West China School of Medicine, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: West China School of Medicine, Sichuan University, Chengdu, China.
authors.forename: L
authors.initials: L
authors.lastname: Lei
authors.affiliation: Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: T
authors.initials: T
authors.lastname: Yi
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: S
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C092778:WNT7A protein, human; D051153:Wnt Proteins