Extracellular signal regulated kinases, ERK1/2 and ERK5, are activated by asbestos fibers in mesothelial and airway epithelial cells and play critical roles in cell survival. ERK1/2-dependent Fra-1 expression is also linked causally to morphologic transformation of rat mesothelial cells and expression of genes (c-met, cd44) stimulating cell proliferation and migration. We hypothesize that activation of ERK1/2 and ERK5 signaling pathways occur by carcinogenic fibers (asbestos, erionite) in the pathogenesis of human malignant mesothelioma (MM) and are potentiated by SV40 in a co-carcinogenic manner. Recent exciting data also suggest that these survival pathways are activated in MMs after exposure to chemotherapeutic drugs and can be manipulated to achieve increased cell killing. Thus, we also hypothesize that ERK1/2 and ERK5 pathways contribute, alone or cooperatively, to MM cell survival after chemotherapy.
In Aim 1, we will test crocidolite and chrysotile asbestos, well-characterized Turkish erionite (see Project 1), and their nonfibrous analogs, alone and with co-exposures to SV40 to determine if ERK1/2, and ERK5 activity, fos/jun family members, and AP-1 transactivation correlate with patterns of transformation and carcinogenicity as determined in the in vitro/in vivo models developed by Dr. Carbone (Core C).
In Aim 2, we will use a panel of SV40+ and - MMs from Core B to determine the effects of dominant negative constructs and small hairpin (sh) RNA interference (RNAi) vectors targeting ERK1/2 and ERK5 on parameters of in vitro cell transformation and survival after treatment with Carmustine (BCNU). In collaboration with Dr. Testa (Project 3) we will also determine if the AKT survival pathway is modified in these studies.
In Aim 3, a mouse orthotopic model will be used to determine if SV40+ and - MMs stably transfected with shMEKI, shERKS or both constructs before intrapleural injection and administration of Carmustine, have altered growth and metastases. Identifying the pathways of cell survival in the pathogenesis of MMs is highly significant for prevention and treatment of these devastating tumors. This Program Project allows our previous mechanistic studies in rodent mesothelioma models to be validated in human mesotheliomas and provides us with expertise on virology and MM pathology (Dr. Carbone), AKT survival pathways (Dr. Testa) and use of normal human mesothelial and MM cells (Dr. Pass).

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Hawaii
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Napolitano, A; Pellegrini, L; Dey, A et al. (2016) Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene 35:1996-2002
Bononi, Angela; Napolitano, Andrea; Pass, Harvey I et al. (2015) Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies. Expert Rev Respir Med 9:633-54
Baumann, Francine; Buck, Brenda J; Metcalf, Rodney V et al. (2015) The Presence of Asbestos in the Natural Environment is Likely Related to Mesothelioma in Young Individuals and Women from Southern Nevada. J Thorac Oncol 10:731-7
Baumann, Francine; Flores, Erin; Napolitano, Andrea et al. (2015) Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis 36:76-81
Baumann, Francine; Buck, Brenda J; Metcalf, Rodney V et al. (2015) Reply to ""No Increased Risk for Mesothelioma in Relation to Natural-Occurring Asbestos in Southern Nevada"". J Thorac Oncol 10:e64-5
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Ou, Sai-Hong Ignatius; Moon, James; Garland, Linda L et al. (2015) SWOG S0722: phase II study of mTOR inhibitor everolimus (RAD001) in advanced malignant pleural mesothelioma (MPM). J Thorac Oncol 10:387-91
Yang, H; Pellegrini, L; Napolitano, A et al. (2015) Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression. Cell Death Dis 6:e1786
Nasu, Masaki; Emi, Mitsuru; Pastorino, Sandra et al. (2015) High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma. J Thorac Oncol 10:565-76
Menges, Craig W; Kadariya, Yuwaraj; Altomare, Deborah et al. (2014) Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis. Cancer Res 74:1261-1271

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