NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma

Our plain-English summary of NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma, by H. Yang, S.R.R. Hall, B. Sun, et al (Cancers, 2021).

The study

• Authors: H. Yang, S.R.R. Hall, B. Sun, L. Zhao, Y. Gao, R.A. Schmid, S.T. Tan, R.W. Peng, F. Yao
• Journal: Cancers
• Published: 2021;13(7)
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.

In plain English

This molecular study of malignant pleural mesothelioma (MPM) tumors did not examine asbestos exposure. The authors reanalyzed public datasets, chiefly The Cancer Genome Atlas MPM cohort (87 tumors; protein data for 61), and tested a drug on cell lines. NF2 mutations lowered NF2 protein but were not associated with altered phosphorylated YAP, a marker of Hippo-YAP pathway activity. LATS2 alterations, by contrast, significantly lowered it. Lower NF2 went with weaker B-cell signaling genes. YAP activation went with higher PD-L1 and T-cell immune genes, read by the authors as a mix of activated and exhausted T cells. In a separate MPM dataset, a T-cell gene score correlated with a YAP/TAZ activity score (Spearman R = 0.54) but not with NF2 gene expression. In a retrospective analysis of patients with various cancers given immune checkpoint blockade, LATS1/2 mutations, rather than NF2 mutations, predicted better overall survival. MPM cells with LATS1/2 mutations were the most sensitive to dasatinib. The authors concluded that NF2 loss and Hippo-YAP dysregulation define distinct MPM subsets. They listed small sample size and lack of validation as limitations.

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: Secondary analysis of public genomic, protein and drug-sensitivity datasets (weighted gene co-expression network analysis), with laboratory cell viability tests on MPM cell lines
• Who was studied: TCGA malignant pleural mesothelioma tumor samples (transcriptomic data for 87, protein array data for 61 of the 87); an independent MPM dataset (GSE29354); a panel of MPM cell lines plus the Met-5A mesothelial cell line; public pan-cancer and cancer cell line datasets; a cBioPortal cohort of cancer patients treated with immune checkpoint blockade
• Exposure: No asbestos or other environmental exposure was studied. The factors analyzed were genetic alterations and protein levels of NF2, LATS1/2 and phosphorylated YAP in tumors, and drug treatment (dasatinib) of cell lines.
• Main results:
  • In TCGA MPM tumors, NF2 mutation was not associated with altered phospho-YAP (S127), and NF2 and p-YAP protein levels were not correlated
  • In TCGA MPM tumors, genetic alterations of LATS2 caused a significant downregulation of p-YAP (S127)
  • A gene module positively correlated with NF2 protein (pink module, 351 genes; r = 0.35; p = 0.001) was enriched for B-cell receptor signaling genes, suggesting low expression of these genes in NF2-defective tumors
  • A gene module negatively correlated with p-YAP (red module, 476 genes; r = −0.39; p = 0.004) was enriched for T-cell-mediated immune genes, including the exhaustion-related checkpoint TIGIT. PD-L1 was significantly negatively correlated with p-YAP, and LATS1/2-mutant tumors had higher PD-L1.
  • The authors interpreted these data as showing that a mix of activated and exhausted T cells in MPM samples is associated with activated YAP signaling
  • In the independent MPM dataset (GSE29354), the red-module hub gene score correlated with the YAP/TAZ target score (Spearman R = 0.54, p = 3.6 times 10 to the minus 5) but not with NF2 gene expression (Spearman R = –0.14, p = 0.33)
  • In a retrospective analysis of cancer patients receiving immune checkpoint blockade (LATS1/2 mutations n = 92; LATS1/2, MST1 or YAP1 mutations n = 111), mutations of LATS1/2, rather than of NF2, predicted better overall survival
  • Among the MPM cell lines tested, those with LATS1/2 mutation were the most sensitive to dasatinib
  • In survival analyses of TCGA MPM patients, YAP/TAZ score and p-YAP protein level, but not NF2, were prognostic (log-rank p = 0.00064 for YAP/TAZ score, p = 0.02 for p-YAP, p = 0.23 for NF2)
  • In MPM with low NF2 expression, a high plasma B-cell infiltrative signature predicted better overall survival
• The authors' conclusion: The authors concluded that NF2 loss-of-function and dysregulated Hippo-YAP signaling have different molecular aberrations and treatment implications in MPM. They proposed that patients with an aberrant Hippo-YAP pathway may benefit from combined BCR-ABL-targeted therapy and immune checkpoint blockade, such as dasatinib with anti-PD-L1.
• Limitations the authors state:
  • Lack of experimental and cohort validation of the findings
  • Small sample size

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, PD-L1, checkpoint inhibitors, Overall Survival, Prognosis.

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