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

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.

<p>Structural and Functional Overview of TEAD4 in Cancer Biology</p>

“…42 On the other hand, a mutation of the TEA domain has been demonstrated to abolish the association of TEAD4 with target genes, impairing TEAD4 transcriptional activity, indicating that the TEAD-DNA interplay is also a druggable target. 17 Furthermore, verteporfin can suppress the progression of ovarian cancer 73 and inhibit the tumorigenic characteristics of gastric cancer stem cells by suppressing the TEAD-YAP interaction.- 74 Amlexanox can target IRF3 to inhibit gastric cancer progression, 44 but targeting the cooperative transcription factors of TEAD4 requires further investigation.…”

“…For instance, several miRNAs were identified to be involved in the inhibition of TEAD4 in gastric cancer and lung cancer. [72][73][74][75][76][77][78][79] Additionally, TEAD4 can activate lncRNA MNX1-AS1 to promote gastric cancer progression through EZH2/ BTG2 and miR-6785-5p/BCL2 axes. 80 The greatest advantage of ncRNA-based therapies over other approaches is their ability to target multiple genes in a variety of pathways, thereby making them efficient regulators of several cellular processes.…”

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

“…Verteporfin is an FDA-approved drug marketed under the name of Visudyne for the treatment of patients with certain serious eye conditions [111]. It has shown good results in different cancer models including liver, pancreatic, gastric and head and neck [27,[112][113][114][115], and is under clinical trials for prostate and breast cancer (ClinicalTrials.gov Identifier NCT03067051 and NCT02872064, respectively). However, clinical trials are based on the photodynamic properties of the drug and Verteporfin is used there as a photosensitizer.…”

Gastric Cancer Stem Cells: Current Insights into the Immune Microenvironment and Therapeutic Targets

“…The transcriptional hippo pathway coactivator YAP1 upregulates sox9 expression to endow CSC properties to esophageal cancer cells [70]. Supporting these previous findings, verteporfin, which is a known YAP inhibitor, can inhibit the tumorigenic properties of GCSCs by targeting YAP1/TAZ-TEAD transcriptional activity [71]. In addition to targeting YAP1, verteporfin can downregulate the expression of heat shock protein 90 beta (HSP90) client proteins by blocking clusterin gene expression, resulting in cell death in GCSCs [72].…”