The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype

Our plain-English summary of The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype, by S. Kandasamy, G. Adhikary, E.A. Rorke, et al (Molecular Cancer Research, 2020).

The study

• Authors: S. Kandasamy, G. Adhikary, E.A. Rorke, J.S. Friedberg, M.B. Mickle, H.R. Alexander, R.L. Eckert
• Journal: Molecular Cancer Research
• Published: 2020;18(3):343-351
• Cited by: 55 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is an aggressive cancer that has a poor prognosis. Tumors develop in the mesothelial lining of the pleural and peritoneal cavities in response to asbestos exposure. Surgical debulking followed by chemotherapy is initially effective, but this treatment ultimately selects for resistant cells that form aggressive and therapy-resistant recurrent tumors. Mesothelioma cancer stem cells (MCS) are a highly aggressive subpopulation present in these tumors that are responsible for tumor maintenance and drug resistance. In this article, we examine the impact of targeting YAP1/TAZ/TEAD signaling in MCS cells. YAP1, TAZ, and TEADs are transcriptional mediators of the Hippo signaling cascade that activate gene expression to drive tumor formation. We show that two YAP1 signaling inhibitors, verteporfin and CA3, attenuate the MCS cell phenotype. Verteporfin or CA3 treatment reduces YAP1/TEAD level/activity to suppress MCS cell spheroid formation, Matrigel invasion, migration, and tumor formation. These agents also increase MCS cell apoptosis. Moreover, constitutively active YAP1 expression antagonizes inhibitor action, suggesting that loss of YAP1/TAZ/TEAD signaling is required for response to verteporfin and CA3. These agents are active against mesothelioma cells derived from peritoneal (epithelioid) and patient-derived pleural (sarcomatoid) mesothelioma, suggesting that targeting YAP1/TEAD signaling may be a useful treatment strategy. IMPLICATIONS: These studies suggest that inhibition of YAP1 signaling may be a viable approach to treating mesothelioma.

©2019 American Association for Cancer Research.

In plain English

This was a laboratory study using mesothelioma cells grown in dishes and tumors grown in mice. It did not study people or asbestos exposure. The authors tested two drugs, verteporfin and CA3, that block a cell-signaling pathway called YAP1/TAZ/TEAD. They tested them on mesothelioma cancer stem cells, an aggressive subset of tumor cells. They used two cell lines: Meso-1, from an epithelioid peritoneal mesothelioma, and NCI-Meso-17, from a sarcomatoid pleural mesothelioma. In both lines, the drugs destroyed or shrank ball-shaped clusters of cancer cells. They also reduced the cells' ability to invade a gel and to move, lowered several pathway proteins including YAP1, and increased markers the authors read as cell death. Mice were injected with stem cells from Meso-1, with 5 female mice per treatment group. In these mice, both drugs reduced tumor growth compared with controls. Cutting YAP1 levels reduced invasion. In Meso-1 cells, a constantly active form of YAP1 counteracted the drugs' suppression of gel invasion. The authors described the reversal for verteporfin as partial. The authors concluded that drugs targeting YAP1/TEAD may be useful in treating mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell culture experiments plus a mouse tumor (xenograft) experiment
• Who was studied: Two human mesothelioma cell lines: Meso-1 (from malignant epithelioid peritoneal mesothelioma) and NCI-Meso-17 (from malignant sarcomatoid pleural mesothelioma). Also NSG mice injected with stem cells derived from Meso-1, 5 female mice per treatment group, each injected in both front flanks.
• Exposure: No asbestos exposure was studied; asbestos is mentioned only as background. Cells and mice were treated with two YAP1 signaling inhibitors, verteporfin and CA3. In mice, verteporfin was given at three dose levels and CA3 at one, by injection into the abdomen three times a week. Dose units may be damaged in the text.
• Main results:
  • In Meso-1 cells, verteporfin destroyed preformed cell clusters (spheroids) and reduced their number.
  • In Meso-1 cells, verteporfin also suppressed cell migration and Matrigel invasion.
  • In Meso-1 spheroids, verteporfin reduced LATS1, LATS1-P and YAP1 levels, while TAZ and pan-TEAD levels slightly increased.
  • In NCI-Meso-17 (pleural) cells, verteporfin reduced spheroid size, invasion and migration.
  • In NCI-Meso-17 cells, CA3 destroyed preformed spheroids and suppressed invasion and migration. In both cell lines it reduced YAP1/TAZ signaling proteins and increased apoptosis markers.
  • In mice, verteporfin produced a dose-dependent reduction in tumor formation. The reduction in tumor size compared with control was reported as significant (P < 0.005).
  • In verteporfin-treated mouse tumors, TAZ and pan-TEAD levels were reduced but YAP1 level was not.
  • In mice, CA3 also reduced tumor formation.
  • Reducing YAP1 with siRNA reduced Matrigel invasion in both cell lines.
  • In Meso-1 cells, a constitutively active form of YAP1, YAP(S127A), antagonized CA3 suppression of Matrigel invasion. It also partially reversed the suppression seen with verteporfin.
• The authors' conclusion: The authors concluded that drugs targeting YAP1/TEAD may be useful in treating mesothelioma. They suggested further experiments combining these inhibitors with chemotherapy.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, STEM, Prognosis, Asbestos Exposure, Chemotherapy, Apoptosis, Epithelioid, Sarcomatoid.

Related studies

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• Targeting YAP in malignant pleural mesothelioma — W.Q. Zhang, Y.Y. Dai, et al. (2017)
• Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling — J. Wu, A.M. Minikes, et al. (2019)
• LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade — I. Tanaka, H. Osada, et al. (2015)
• Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis — C.W. Menges, Y. Kadariya, et al. (2014)
• Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis — S. Luanpitpong, L. Wang, et al. (2014)

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