Role of Merlin/NF2 inactivation in tumor biology

Our plain-English summary of Role of Merlin/NF2 inactivation in tumor biology, by A.M. Petrilli, C. Fernández-Valle (Oncogene, 2016).

The study

• Authors: A.M. Petrilli, C. Fernández-Valle
• Journal: Oncogene
• Published: 2016;35(5):537-48
• Type of article: Review
• Cited by: 359 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Merlin (Moesin-ezrin-radixin-like protein, also known as schwannomin) is a tumor suppressor protein encoded by the neurofibromatosis type 2 gene NF2. Loss of function mutations or deletions in NF2 cause neurofibromatosis type 2 (NF2), a multiple tumor forming disease of the nervous system. NF2 is characterized by the development of bilateral vestibular schwannomas. Patients with NF2 can also develop schwannomas on other cranial and peripheral nerves, as well as meningiomas and ependymomas. The only potential treatment is surgery/radiosurgery, which often results in loss of function of the involved nerve. There is an urgent need for chemotherapies that slow or eliminate tumors and prevent their formation in NF2 patients. Interestingly NF2 mutations and merlin inactivation also occur in spontaneous schwannomas and meningiomas, as well as other types of cancer including mesothelioma, glioma multiforme, breast, colorectal, skin, clear cell renal cell carcinoma, hepatic and prostate cancer. Except for malignant mesotheliomas, the role of NF2 mutation or inactivation has not received much attention in cancer, and NF2 might be relevant for prognosis and future chemotherapeutic approaches. This review discusses the influence of merlin loss of function in NF2-related tumors and common human cancers. We also discuss the NF2 gene status and merlin signaling pathways affected in the different tumor types and the molecular mechanisms that lead to tumorigenesis, progression and pharmacological resistance.

In plain English

This was a narrative review of published work on merlin, the tumour suppressor protein encoded by the NF2 gene, and the consequences of its loss or inactivation in tumours. The authors described NF2-related tumours (vestibular and other schwannomas, meningiomas, ependymomas) and the signalling pathways reported to be altered when merlin is lost, including CD44/Rac1/PAK, Ras, PI3K/Akt/mTOR and the mammalian hippo (YAP/LATS/CRL4-DCAF1) pathway. A separate section reviewed malignant mesothelioma, which the authors stated is primarily caused by exposure to asbestos, noting that somatic NF2 mutations have been reported in a large percentage of mesothelioma patients and that merlin was phosphorylated at Ser518 (inactive form) in patients without detectable NF2 mutations. The authors recounted mouse studies in which Nf2 hemizygosity was associated with increased susceptibility to asbestos-induced mesothelioma, and cell-line work linking merlin loss to PAK1, Akt, mTORC1, FAK-Src and hippo pathway changes. Other cancers reviewed included breast, colorectal, hepatobiliary, prostate, glioblastoma, medullary thyroid carcinoma and melanoma, where NF2 mutation was linked to drug resistance.

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: narrative review of published literature
• Who was studied: Published studies of human tumours, tumour cell lines and genetically modified mice relating to NF2/merlin; no new patients or specimens were studied
• Exposure: NF2 gene mutation, deletion or epigenetic/post-translational inactivation of merlin; for mesothelioma, asbestos exposure (crocidolite fibres in the cited mouse studies)
• Main results:
  • The review reported that somatic NF2 mutations occur in a large percentage of malignant mesothelioma patients, and that in mesothelioma patients without detectable NF2 mutations merlin was phosphorylated at Ser518, an inactive tumour suppressor state
  • Reviewed mouse work: Nf2 hemizygosity was reported to increase susceptibility to asbestos-induced mesothelioma in Nf2KO3/+ mice given crocidolite asbestos, with peritoneal mesothelioma cells showing homozygous Nf2 inactivation; a second Nf2(+/-) line treated with asbestos showed frequent Nf2 homozygous deletions
  • Reviewed cell-line work: in eleven malignant mesothelioma cell lines mTORC1 activation was found, and rapamycin selectively inhibited proliferation of seven merlin-null mesothelioma cell lines but not merlin-positive lines
  • Reviewed finding in pleural mesothelioma: elevated YAP1 in malignant pleural mesothelioma samples, and YAP1 silencing reduced growth of NCI-H290 cells carrying NF2 homozygous deletion
  • Reviewed finding in sporadic nervous system tumours: merlin expression on western blot was highly reduced or absent in 11 of 14 sporadic schwannomas, 16 of 19 sporadic meningiomas and 3 of 8 sporadic ependymomas
  • Reviewed finding on other cancers: mutational analysis of 315 human carcinoma samples found a low prevalence of NF2 mutations, 2.2% in hepatocellular, acute myelogenous leukemia and squamous cell lung carcinomas
• The authors' conclusion: The authors concluded that although NF2 mutations are not frequent in common human malignant cancers, when present they can affect disease progression, therapeutic approach or prognosis, and that combinatorial molecular therapy may be the most successful approach, with further research still required
• Limitations the authors state:
  • The authors stated that a better understanding of the role of merlin loss or inactivation in tumorigenesis and tumour progression is still required
  • The authors stated that comprehensive studies of promoter methylation and related epigenetic mechanisms have not been addressed for NF2/merlin in NF2-tumours or common cancers
  • The authors noted discrepancies between mouse knock-out models and the human disease, attributed to genome/proteome, physiological and lifespan differences and to timing of merlin inactivation

Topics

Medical terms in this study, explained in our Lexicon: Merlin, Bilateral, Mesothelioma, Carcinoma, Prognosis, Carcinogenesis.

Related studies

• Functional inactivation of NF2/merlin in human mesothelioma — C. Thurneysen, I. Opitz, et al. (2009)
• NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma — T. Sato, Y. Sekido (2018)
• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival — I. Stamenkovic, Q. Yu (2010)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)
• Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer — N.R. Shah, I. Tancioni, et al. (2014)

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