A recent publication by Sekido and colleagues has highlighted the connection between two relevant survival/growth pathways in mesothelioma, TGF-beta and NF2/Hippo.

TGF-beta may play important roles in the immune regulation of mesothelioma and in the production of extracellular matrix.
NF2 (neurofibromatosis type 2; Merlin) gene or downstream signaling molecules of the Hippo signaling cascade contain inactivating mutations in nearly 75% of MM cases.

In this article, transcriptional deregulation, mediated by inactivation of the nuclear deubiquitinase BAP1, is implicated in the pathogenesis of mesothelioma.  The two most common known genetic alterations in mesotheliomas are 9p21 deletions on CDKN2A and 22q deletions causing NF2 loss. The authors show that another gene with a high rate of non-synonymous mutations is BAP1 (encoding BRCA1-associated protein 1).  Somatic mutations were found in 23% of mesotheliomas.  The study also shows that other common tumor suppressors, such as PTEN and p53, showed few or no mutations, confirming data from previous …

Here is a paper by Deborah Altomare analyzing Ink4A and Arf role in mesothelioma pathogenesis.
p16(INK4A) and p14(ARF) are frequently co-deleted in human malignant mesothelioma and the authors here find that in vivo both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while the inactivation of Arf appears to be crucial for mesothelioma pathogenesis, the inactivation of both p16(INK4A) and p19(ARF) cooperate to accelerate asbestos-induced tumorigenesis.

The Nf2 gene is mutated in 40% of mesotheliomas and and disruption of the Nf2/Merlin signaling is key to Anton Berns’ murine mesothelioma model. The authors here propose that Merlin suppresses tumorigenesis by translocating to the nucleus and by inhibiting CRL4(DCAF1), an E3 ubiquitin ligase. This breakthrough finding opens up a new candidate drug target for the treatment of NF2 tumors – especially because many patients have gene mutations that affect this cell signaling pathway at various levels.