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

Int J Cancer. 2020 Apr 15;146(8):2255-2267. doi: 10.1002/ijc.32667. Epub 2019 Sep 30.

Abstract

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.

Keywords: CD44; CSC; gastric carcinoma; hippo pathway; patient-derived xenografts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm
  • Humans
  • Hyaluronan Receptors / biosynthesis
  • Hyaluronan Receptors / genetics
  • Male
  • 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
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects
  • Up-Regulation
  • Verteporfin / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • CD44 protein, human
  • DNA-Binding Proteins
  • Hyaluronan Receptors
  • Nuclear Proteins
  • TEAD1 protein, human
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • YAP1 protein, human
  • Verteporfin