NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition
Authors: Julio C Ricarte-Filho
Iňigo Landa
Filippo Giancotti
Jeffrey A Knauf
Ronald Ghossein
Yuqiang Fang
Suresh C Jhanwar
Agnes Viale
Adriana Heguy
Brian R Untch
Barry S Taylor
Ian Ganly
Vicki E Smith
Yogindra Persaud
Kety H Huberman
Francesca Voza
Maria E R Garcia-Rendueles
Gisele Oler
James A Fagin
Journal: Cancer discovery (2015)
Discipline: CLINICAL MEDICINE
Keywords: Ch22q LOH; RAS mutations; thyroid cancer; NF2; merlin
Affiliations: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York., Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. .

Abstract:  Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. Significance: Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors. 

Retracted: No

PubPeer comments:
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 #4 In the paper the same ACTIN was paired with three different MERLIN blots. How is that going to be corrected? , 
 Thank you for pointing this out. We can explain this, and are preparing a detailed response. Jim Fagin , 
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 We repeated the merlin hybridization on each of these blots, as we illustrate in the additional blots we sent to you, as well as the actin. We could replace the corresponding actin to each blot, but is this necessary based on the evidence that we showed: i.e. that they are all from the same lysate, and that the actins were done and appropriately loaded? I will confer with the editors of Cancer Discovery and make a correction if they believe it is necessary. , 
 2019 correction. https: cancerdiscovery.aacrjournals.org content 9 11 1628 In the original version of this article (1), the same Actin loading control Western blot was shown for shNF2 clone M2 in C643 cells in Figs. 2C, 3C, and 4A. Aliquots of the same shNF2 clone M2-transduced C643 cell lysate were used for multiple different blots used in Figs. 2C, 3C, and 4A, and the Actin blot presented was intended to be a representative Actin loading control. The figures and figure legends have been corrected in the latest online HTML and PDF versions of the article to show the same representative Merlin and Actin blots from the shNF2 clone M2-transduced C643 cell lysate for Figs. 2C, 3C, and 4A. The figure legends have also been corrected in the latest online HTML and PDF versions of the article to indicate that the same representative Merlin and Actin Western blots for shNF2 clone M4 in C643 cells are shown in Figs. 2C and 3C because aliquots of the same shNF2 clone M4-transduced C643 cell lysate were used for all blots in these figure panels. Individual blots and corresponding Actin controls for all blots shown in Figs. 2C, 3C, and 4A are now included in a new Supplementary Fig. S11. The authors apologize for any confusion caused by the original figures. Reference 1.u21b5Garcia-Rendueles MER, Ricarte-Filho JC, Untch BR, Landa I, Knauf JA, Voza F, et al. NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition. Cancer Discov 2015;5:1178u201393. ,