Joseph R. Testa, PhD
Office Phone: 215-728-2610
Dr. Testa’s laboratory investigates the role of hereditary and somatic mutations in malignant mesothelioma, a cancer of the cells lining the chest and abdominal cavities, primarily caused by exposure to asbestos. His group discovered frequent mutations of the CDKN2A/ARF locus, a region of DNA that encodes the tumor suppressors p16INK4a and p14ARF, and NF2 in human mesothelioma. In 2011, he and his collaborators also discovered germline mutations of the BAP1 tumor suppressor gene in two families with a high incidence of mesothelioma, the first study demonstrating that inherited mutations can influence a person’s risk of mesothelioma. Besides mesothelioma, some of the BAP1 mutation carriers developed ocular melanoma or other cancers, and this cancer susceptibility is now recognized as the BAP1 Syndrome. Dr. Testa’s laboratory's current work on mesothelioma focuses on investigating the various molecular signaling pathways that are hyper-activated in this disease in order to identify novel druggable targets for cancer therapy or prevention.
The Testa laboratory also developed the first mouse model that faithfully reproduces many of the molecular features of human mesothelioma, which allows them to better understand mesothelioma tumor development and even test new therapies that could later be used in humans. This mouse model is particularly useful since it demonstrates many characteristics common to the human form of the disease, including frequent inactivation of the Nf2 and Cdkn2a/Arf tumor suppressor genes, and hyper-activation of the enzyme Akt (AKT in humans), which plays a central role in the creation and progression of tumors.
Dr. Testa has a longstanding interest in the oncogenic role of AKT, beginning with his chromosomal mapping of the AKT1 proto-oncogene in 1988. The Testa laboratory cloned and characterized the related AKT2 gene and provided the first evidence for recurrent alterations of the AKT pathway in human cancers. We now know that genes encoding many components of this pathway, including PI3-kinase and PTEN, are repeatedly mutated in various cancers, leading to hyper-activation of AKT. His group demonstrated that constitutive activation of Akt2 in the mouse thymus results in T-cell lymphomas characterized by chromosome inversion- or translocation-mediated activation of the Dlx5 and Myc oncogenes, respectively, which cooperate with Akt2 to promote oncogenesis. The Testa laboratory also showed that the human homologue, DLX5, is overexpressed in human T-cell lymphomas and ovarian cancers, where it promotes tumor cell proliferation, in part by deregulating MYC. His lab also discovered an AKT2 interactor dubbed APPL1, a novel adaptor now incriminated in multiple signaling pathways.Description of research projects
- Menges CW, Sementino E, Talarchek J, Xu J, Chernoff J, Peterson JR, Testa JR. Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways. Mol Cancer Res. 2012 Sep;10(9):1178-88. PubMed
- Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011 Aug 28;43(10):1022-5. doi: 10.1038/ng.912. PubMed
- Altomare DA, Menges CW, Xu J, Pei J, Zhang L, Tadevosyan A, Neumann-Domer E, Liu Z, Carbone M, Chudoba I, Klein-Szanto AJ, Testa JR. Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. PLoS One. 2011 Apr 19;6(4):e18828. PubMed
- Tan Y, Cheung M, Pei J, Menges CW, Godwin AK, Testa JR. Upregulation of DLX5 promotes ovarian cancer cell proliferation by enhancing IRS2-AKT Signaling. Cancer Res. 2010 Nov 15;70(22):9197-206. PubMed
- Altomare DA, Zhang L, Deng J, Di Cristofano A, Klein-Szanto AJ, Kumar R, Testa JR. GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin Cancer Res. 2010 Jan 15;16(2):486-96. [article featured in journal Highlights section]. PubMed
- Xu J, Testa JR. DLX5 (Distal-less homeobox 5), promotes tumor cell proliferation by transcriptionally regulating MYC. J Biol Chem. 2009 Jul 31;284(31):20593-601. PubMed
- Altomare DA, Menges CW, Pei J, Zhang L, Skele-Stump KL, Carbone M, Kane AB, Testa JR. Activated TNFa/NFkB signaling via down regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3420-5. PubMed