YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition
Authors: Ruiping Wang
Sinchita Roy-Chowdhuri
Makoto Kobayashi
Xiaochuan Dong
George Adrian Calin
Longfei Huo
Zhenning Wang
Yan Xu
Jiankang Jin
Namita Shanbhag
Ju-Seog Lee
Kazuto Harada
Brian D Badgwell
Jody V Vykoukal
Wei Zhao
Ghia Tatlonghari
Ailing Scott
Jaffer A Ajani
Randy L Johnson
Xiaodan Yao
Linghua Wang
Samir M Hanash
Melissa Pool Pizzi
Jeannelyn Santiano Estrella
Lang Ma
Guang Peng
Yuan Li
Shumei Song
Ying Wang
Journal: Gut (2021)
Discipline: CLINICAL MEDICINE
Keywords: gastric adenocarcinoma; gene regulation; molecular oncology.
Affiliations: Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA  ., Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA., Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China., Department of Genomic Medicine, UT MD Anderson Cancer Center, Houston, TX, USA., Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan., Department of Cell Biology, Key Laboratory of Carcinogenesis and Transalational Researcch, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing, China., Department of Pathology, Union Hospital, Tongji Medical College, Huazhong Unversity of Science and Technology, Wuhan, China., Department of Surgery, UT MD Anderson Cancer Center, Houston, TX, USA., Department of Pathology, UT MD Anderson Cancer Center, Houston, TX, USA., Department of Clinical Cancer Prevention, UT MD Anderson Cancer Center, Houston, TX, USA., Department of Molecular Translational Pathology and the Center for RNA interference and Non-coding RNAs, UT MD Anderson Cancer Center, Houston, TX, USA., Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Departmental of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA.

Abstract:  Objective: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 (YAP1) oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target. Methods: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases. Results: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1high PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1high PC cells especially in combination with cytotoxics in vivo PDX model. Conclusions: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC. 

Retracted: No

PubPeer comments:
 A micrograph in Figure 1D has been used two times in Figure 4A, and in one of them it is presented as something else. A micrograph from Figure 6D has been duplicated and presented as something else in Figure 6G. ![file] , 
 Dear Colleagues at PubPeer: Thank you for bringing to our attention duplicated figures. We apologize for this unintended and inadvertent error. We are submitting an Erratum to the journal to correct our error. This has resulted in a change in our standard operating procedure. Before submitting any report for publication revision, we will independently check all figure for possible duplication to avoid such errors. In Fig.1D upper left panel was double stained YAP1 and immune marker CD45 in IP-013 case as one of the representative cases indicating that YAP1 was enriched in tumor cells but not in immune cells, we did stained many ascites cases to support this conclusion; while in Fig.4A, we used IP-013 case as a representative to indicate tumor cells with tumor cell percentage less than 5% but with YAP1 high and EpCAM low none can easily form tumors in nude mice demonstrating the importance of YAP in PC progression and metastases. However, we should not have used the same picture as we had many PC cases with YAP1 CD45 dual staining that we could have used. We will request the journal to replace Fig.1D with another representative case. In addition, for Fig.6D and 6G, we checked the original images for two cases of GA070716 and GA051816 and are ready to contact the editor to replace with the correct image. We appreciate your efforts. Best Regards, Shumei Song ,