Joseph R. Testa, PhD, FACMG
Co-Leader, Cancer Biology Program
Chief, Genomic Medicine
Director, Clinical Cytogenomics Laboratory
Director, Genomics Facility
Scientific Leader, Kidney Cancer Working Group
- Postdoctoral fellow, University of Chicago, Chicago, IL, 1976-1980
- PhD, Biological Sciences, Fordham University, New York, NY, 1976
- BS, MS, Biology, Southern Connecticut State University, New Haven, CT, 1973
- Diplomate (Clinical Cytogenetics), American Board of Medical Genetics, 1987
- Founding Fellow PhD, American College of Medical Genetics & Genomics (FACMG), 1993
- American Association for the Advancement of Science
- American Association for Cancer Research
- American College of Medical Genetics
- American Society of Hematology
- American Society of Human Genetics
- American Society of Microbiology
- Federation of American Societies for Experimental Biology
- International Mesothelioma Interest Group
Honors & Awards
- Pioneer Research Award, Mesothelioma Applied Research Foundation, 2013
- Wagner Medal, International Mesothelioma Interest Group, 2012
- Elected Fellow, American Association for the Advancement of Science, 2012
- The Reimann Honor Award of the Fox Chase Cancer Center, 2011
- Scientific Research Award, American Cancer Society (ACS) Southeast PA Division, 2009
- Co-recipient, Landon Foundation-AACR Innovator Award for International Collaboration in Cancer Research (team award), 2008
- Member, NCI Board of Scientific Counselors, Basic Sciences, 2006-2011
- Irving Selikoff Award for Cancer Research, 1999
- Stohlman Memorial Scholar Award, Leukemia Society, 1987
- Leukemia Society of America Scholar Award, 1984-1990
- Leukemia Society of America Special Fellow Award, 1982-1984
Director, Genomics Facility
Molecular biology of mesothelioma; AKT oncogenic activity
The BAP1 tumor predisposition syndrome.
Molecular genetic basis of malignant mesothelioma susceptibility and progression.
Role of the AKT1/2 oncogenes in tumorigenesis and resistance to anti-cancer therapies.
Characterization of genes that interact with and/or cooperate with AKT kinase activation in tumor development.
Use of genetically engineered mice to assess gene–environment interactions, the role of asbestos-induced inflammation in tumor development, and as preclinical models for selective drug targeting of cellular pathways underpinning human tumorigenesis.
The Testa lab 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. The group discovered frequent mutations of the CDKN2A 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 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 tumor predisposition syndrome. Much of the current work in the lab is focused understanding the mechanisms involved in BAP1-related tumor susceptibility. Using a genetically-engineered mouse (GEM) model they developed, the Testa lab provided the first in vivo evidence that inherited (germline) mutation of Bap1 predisposes to the development of asbestos-induced mesothelioma. This and other Bap1 mouse models are currently being used to assess susceptibility to spontaneous lung formation and gene–environment interactions. The group is also using novel GEM models to unravel the role of asbestos-induced inflammation in the genesis of malignant mesothelioma.
Mechanistic work by the Testa lab previously linked NF2 inactivation to oncogenic PAK and FAK signaling, implicating NF2 inactivation in mesothelioma cell spreading, invasiveness and proliferation, thereby establishing a framework for elucidating tumorigenic mechanisms and novel therapeutic targets in this disease. Other in vivo studies demonstrated that alterations of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive mesotheliomas characterized by enhanced tumor dissemination and the involvement of a cancer stem cell (CSC) population. Mesothelioma is very difficult to treat and almost always recurs after therapy. Based on his work linking NF2 loss to FAK activation, he partnered with investigators in the pharmaceutical industry to test a novel drug that blocks FAK activity. Their findings suggested that FAK inhibitor treatment might be especially beneficial in patients with NF2-deficient tumors. Moreover, the drug proved to be particularly effective at killing CSCs, which can give rise to recurrent tumors. These preclinical studies provided the rationale for a clinical trial in mesothelioma patients using a FAK inhibitor as a single agent after first-line chemotherapy. Other planned preclinical studies involve the use of a FAK inhibitor with inhibitors of other pathways that are commonly activated in human mesotheliomas.
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 lab cloned and characterized the related AKT2 gene and provided the first evidence for recurrent alterations of the AKT pathway in human cancers. The group is currently investigating the role of an AKT interactor, the adapter APPL1/2, in embryonic development and oncogenesis. The lab is also characterizing how other genes, such as the proto-oncogene Myc or the homeobox gene Dlx5 cooperate with Akt2 to promote oncogenesis.
The Testa lab is highly interactive and currently collaborates with, and shares funded grants with, both the Chernoff and Balachandran labs at FCCC, on studies designed to target various kinases aberrantly activated in mesothelioma. Additionally, collaborative grants with Frank Rauscher (Wistar) on BAP1 and Rebecca Simmons (UPenn) on mouse models of asbestos carcinogenicity are ongoing.
Previous lab members
- Debororah Altomare, PhD, Assistant Professor
- Ara Tadevosyan, BS, Scientific Technician I
- Lili Zhang, BS, Scientific Technician
University of Pennsylvania
Tesla, Joesph. Asbestos and Mesothelimoa. Springer, 2017.
Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction. Cheung M, Kadariya Y, Talarchek J, Pei J, et al. Cancer Lett. 2015:369(2):261-5. PMCID: PMC4634709. PubMed
Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, et al. Sci Transl Med. 2014; 6:237ra68. PMCID: PMC4165339 PubMed
Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Xu J, Kadariya Y, Cheung M, Pei J, Talarchek J, et al. Cancer Res. 2014; 74:4388-97. PMCID: PMC4165574. PubMed
Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis. Menges CW, Kadariya Y, Altomare D, Talarchek J, Neumann-Domer E, et al. Cancer Res. 2014; 74:1261-71. PMCID: PMC3945416. PubMed
BAP1 and cancer. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, et al. Nat Rev Cancer. 2013; 13:153-9. PMCID: PMC3792854. PubMed
Losses of both products of the Cdkn2a/Arf locus contribute to asbestos-induced mesothelioma development and cooperate to accelerate tumorigenesis. Altomare DA, Menges CW, Xu J, Pei J, Zhang L, et al. PLoS One. 2011; 6:e18828. PMCID: PMC3079727. PubMed
Testa JR, Cheung M, Pei J, Below JE, Tan Y, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011; 43:1022-5. PMCID: PMC3184199. PubMed
A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice. Tan Y, Timakhov RA, Rao M, Altomare DA, Xu J, et al. Cancer Res. 2008; 68:1296-302. PMID: 18316591. PubMed
Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Poulikakos PI, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, et al. Oncogene. 2006; 25:5960-8. PubMed PMID: 16652148. PubMed
A mouse model recapitulating molecular features of human mesothelioma. Altomare DA, Vaslet CA, Skele KL, De Rienzo A, Devarajan K, et al. Cancer Res. 2005; 65:8090-5. PMID: 16166281. PubMed
p21-activated kinase links Rac/Cdc42 signaling to merlin. Xiao GH, Beeser A, Chernoff J, Testa JR. J Biol Chem. 2002; 277:883-6. PMID: 11719502. PubMed
High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. Bianchi AB, Mitsunaga SI, Cheng JQ, Klein WM, Jhanwar SC, et al. Proc Natl Acad Sci U S A. 1995; 92:10854-8. PMCID: PMC40529. PubMed
AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, et al. Proc Natl Acad Sci U S A. 1992; 89:9267-71. PMID: 1409633 PMCID: PMC50107. PubMed
A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Bellacosa A, Testa JR, Staal SP, Tsichlis PN. Science. 1991; 254: 274-7. PMID: 1833819. PubMed