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.
- gastric adenocarcinoma
- gene regulation
- molecular oncology
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Contributors All coauthors have contributed to this study. Conception and design: SS and JAA; development of methodology: SS, YX, LH, RW, YL and KH. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc): SS, YX, LH, RW, YL, KH, YW, JJ, AS, MPP, WZ, XD, LM, BB, NS, GT, JSE, SR-C, MK, JV and LW. Analysis and interpretation of data (eg, statistical analysis, biostatistics, computational analysis): LW, JAA and SS. Writing, review and/or revision of the manuscript: JAA and SS. Administrative, technical or material support (ie, reporting or organising data, constructing databases): SMH, RLJ, GAC, GP, J-SL, XD and LW. Study supervision: SS. Other (financial support): JAA and SS.
Funding This work was supported by Public Health Service Grant DF56338, which supports the Texas Medical Center Digestive Diseases Center (SS); an MD Anderson Institutional Research Grant (3-0026317 to SS); and grants from Department of Defense (CA160433 to SS); and the National Institutes of Health (CA129906, CA138671 and CA172741 to JAA). Supported in part by the Caporella family, the Park family, the Dallas family, the Dio family, the Frankel family, the Smith family, Anonymous donor, the McNeil family, the Stupid Strong Foundation, Dallas, TX and Gastric Cancer Foundation, San Francisco, CA
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval Ethical approval for this study was obtained from the Institutional Review Board of The University of Texas MD Anderson Cancer Center.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All dataset and materials generated from this study are available for scientific community upon request.