Verteporfin targeting YAP1/TAZ‐TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells

• Published in: International journal of cancer Vol. 146; no. 8; pp. 2255 - 2267
• Main Authors: Giraud, Julie, Molina‐Castro, Silvia, Seeneevassen, Lornella, Sifré, Elodie, Izotte, Julien, Tiffon, Camille, Staedel, Cathy, Boeuf, Hélène, Fernandez, Solène, Barthelemy, Philippe, Megraud, Francis, Lehours, Philippe, Dubus, Pierre, Varon, Christine
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15-04-2020; Wiley Subscription Services, Inc; Wiley
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aldehyde dehydrogenase; Animal models; Animals; Cancer; Carcinoma; CD44; CD44 antigen; Cell Growth Processes - drug effects; Cell Line, Tumor; Cell proliferation; Cell survival; Chemotherapy; CSC; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm; Gastric cancer; gastric carcinoma; hippo pathway; Humans; Hyaluronan Receptors - biosynthesis; Hyaluronan Receptors - genetics; Life Sciences; Male; Medical research; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; patient‐derived xenografts; Stem cell transplantation; Stem cells; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Tumor cells; Tumors; Up-Regulation; Verteporfin - pharmacology; Xenograft Model Antitumor Assays; Xenografts; Yes-associated protein; CSC; hippo pathway; gastric carcinoma; CD44; patient-derived xenografts
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32667

Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation‐44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T‐TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration‐approved drug preventing Y/T‐TEAD interaction, on gastric CSC tumorigenic properties. Y/T‐TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient‐derived GC and cell lines. Verteporfin effects on Y/T‐TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient‐derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T‐TEAD molecular signature was enriched in CD44+ patient‐derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T‐TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere‐forming CD44+/aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T‐TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ‐TEAD activity could be a promising CSC‐based strategy for the treatment of GC.
What's new?
In gastric cancer, populations of cancer stem cells (CSCs), which initiate and sustain tumor growth and drive tumor recurrence, are maintained through activity of the yes‐associated protein 1 (YAP1), TAZ, and TEA domain transcription factor (TEAD) complex. In this study, employing gastric cancer models, transcriptional activity of the YAP1/TAZ‐TEAD complex was successfully inhibited by the benzoporphyrin derivative verteporfin. Specifically, verteporfin decreased the pool of gastric CSCs in vitro and in vivo and inhibited tumor growth in patient‐derived gastric cancer xenografts. The results suggest that targeting YAP1/TAZ‐TEAD activity with verteporfin is a promising therapeutic strategy for gastric cancer.