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Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas
J Cell Physiol. 2018 Nov;233(11) :8952-8961
PMID: 29904909    PMCID: PMC6168364    URL: https://www.ncbi.nlm.nih.gov/pubmed/29904909
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Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. Pten(L/L) ;Tp53(L/L) mice injected intraperitoneally or intrapleurally with adenovirus-expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt-mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.
1097-4652 Sementino, Eleonora Menges, Craig W ORCID: http://orcid.org/0000-0002-8305-9811 Kadariya, Yuwaraj Peri, Suraj Xu, Jinfei Liu, Zemin Wilkes, Richard G Cai, Kathy Q Rauscher, Frank J 3rd Klein-Szanto, Andres J Testa, Joseph R ORCID: http://orcid.org/0000-0003-1301-5175 R01 CA175691/CA/NCI NIH HHS/United States Journal Article United States J Cell Physiol. 2018 Jun 15. doi: 10.1002/jcp.26830.