NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity

Our plain-English summary of NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity, by D. Xu, S. Yin, Y. Shu (NPJ Precision Oncology, 2024).

The study

• Authors: D. Xu, S. Yin, Y. Shu
• Journal: NPJ Precision Oncology
• Published: 2024;8(1):133
• Type of article: Review
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Neurofibromatosis type 2 (NF2) is a tumor suppressor gene implicated in various tumors, including mesothelioma, schwannomas, and meningioma. As a member of the ezrin, radixin, and moesin (ERM) family of proteins, merlin, which is encoded by NF2, regulates diverse cellular events and signalling pathways, such as the Hippo, mTOR, RAS, and cGAS-STING pathways. However, the biological role of NF2 in tumorigenesis has not been fully elucidated. Furthermore, cross-cancer mutations may exert distinct biological effects on tumorigenesis and treatment response. In addition to the functional inactivation of NF2, the codeficiency of other genes, such as cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B), BRCA1-associated protein-1 (BAP1), and large tumor suppressor 2 (LATS2), results in unique tumor characteristics that should be considered in clinical treatment decisions. Notably, several recent studies have explored the metabolic and immunological features associated with NF2, offering potential insights into tumor biology and the development of innovative therapeutic strategies. In this review, we consolidate the current knowledge on NF2 and examine the potential connection between cancer metabolism and tumor immunity in merlin-deficient malignancies. This review may provide a deeper understanding of the biological roles of NF2 and guide possible therapeutic avenues.

© 2024. The Author(s).

In plain English

This article was a review, not a new study. The authors gathered published research on NF2, a tumor suppressor gene whose protein is called merlin, and its role in tumors including mesothelioma, schwannomas and meningioma. They described the cell signalling pathways merlin takes part in. They also covered gene changes that occur together with NF2 loss, such as CDKN2A/B, BAP1 and LATS2, and how NF2 loss may relate to tumor metabolism and the immune system. Asbestos appeared only briefly. The review described malignant pleural mesothelioma as closely associated with asbestos exposure and cited a mouse study in which Nf2 inactivation contributed to mesothelioma after asbestos exposure. One earlier mouse study it summarized reported mesothelioma in 2 of 15 mice with Nf2 knocked out alone, in 7 of 42 with Nf2 and Bap1 knocked out, and in 22 of 26 with Bap1, Nf2 and Cdkn2a knocked out. The authors wrote that the effectiveness of targeted drugs for NF2-associated tumors has been controversial. They concluded that targeted therapy is still lacking and that more research is needed.

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 research on the NF2 gene in tumors; no new patient data
• Who was studied: No study population; the review covered published laboratory, animal and clinical research on NF2-related tumors, mainly mesothelioma, schwannomas and meningioma
• Exposure: The review's subject was loss or mutation of the NF2 gene, not asbestos. Asbestos was mentioned only in passing as closely associated with malignant pleural mesothelioma; no fiber types were named.
• Main results:
  • The review cited earlier work reporting that approximately 30–50% of somatic mutations in NF2 occur in pleural mesotheliomas (wording as printed).
  • The review cited a mouse study in which inactivation of Nf2 in hemizygous mice contributed to mesothelioma formation after asbestos exposure.
  • In a cited mouse study (Kukuyan et al.), malignant mesothelioma occurred in 2 of 15 mice with Nf2 knocked out alone.
  • In the same cited study, malignant mesothelioma occurred in 16.6% (7 of 42) of mice with Nf2 combined with Bap1 loss.
  • In the same cited study, malignant mesothelioma occurred in 84.6% (22 of 26) of mice lacking Bap1, Nf2 and Cdkn2a.
  • In cited datasets of malignant pleural mesothelioma patients (TCGA, n = 86; MSK-IMPACT, n = 61), combined CDKN2A/B and NF2 alterations were found in 8% (n = 7) and 5% (n = 3) of patients respectively. The review reported that these alterations were associated with poor survival.
  • In a cited study of peritoneal mesothelioma, 13% of cases had homozygous CDKN2A deletions together with hemizygous NF2 loss. The review described this as a negative prognostic factor for progression-free and overall survival.
  • In a cited single-arm phase II trial of 59 malignant pleural mesothelioma patients, everolimus yielded less favourable outcomes than other agents.
  • The authors described the effectiveness of targeted therapy for NF2-associated tumors as controversial.
  • The review cited a phase III trial in malignant pleural mesothelioma comparing ipilimumab plus nivolumab with pemetrexed and platinum. It reported a statistically significant improvement in overall survival (18.1 versus 14.1 months, p = 0.002), described as particularly in the nonepithelial subtype.
• The authors' conclusion: The authors concluded that targeted therapy for tumors with altered NF2 is still lacking. They said further research into the underlying mechanisms is needed to determine whether targeted therapy or immunotherapy could improve prognosis.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Suppressor Gene, Mesothelioma, Merlin, Carcinogenesis, CDKN2A, BAP1.

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• Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma — C. Pulito, E. Korita, et al. (2019)
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• Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma — I. Fiorilla, S. Martinotti, et al. (2023)

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