Genomic alterations and perturbations of key cellular pathways involved in cell cycling and survival are hallmarks of human cancer. Certain chromosomal changes, mainly balanced reciprocal translocations, are consistently associated with specific types of leukemias, lymphomas, and sarcomas. Some of these translocations result in the altered expression of dominantly acting oncogenes located at or very near the site of chromosomal exchange. Other translocations produce fusion genes that encode aberrant, oncogenic proteins. In many of these malignancies, such balanced rearrangements are the only cytogenetic abnormality present. In contrast, in the common epithelial tumors of adults, such as lung and ovarian carcinomas, the karyotypes typically display numerous genomic changes, including amplification of oncogenes and chromosomal deletions. Some of the recurrent deletions encompass sites of tumor suppressor genes, whose loss and/or inactivation play a fundamental role in tumorigenesis. A primary goal of our research is to understand the biological implications of recurrent genomic alterations occurring in malignant mesotheliomas (MMs), highly aggressive tumors that arise from the mesothelial cell lining of the pleural, peritoneal, and pericardial cavities. Exposure to asbestos is considered the primary cause of MM, although the oncogenic DNA virus SV40 and hereditary factors have also been implicated.
We and others have shown that MMs exhibit frequent mutation of the NF2 tumor suppressor gene, encoding a protein known as merlin, and homozygous deletion of the INK4a/ARF locus, which encodes the tumor suppressors p16INK4a and p14ARF. Loss of p16INK4a and p14ARF result in impairment of the pRb and p53 pathways, respectively. Current work in our laboratory focuses on understanding the role of merlin in regulating Rac/Cdc42/Pak1 signaling and how merlin inactivation contributes to cell cycle progression and tumor cell invasiveness.
We are also using mouse models to identify genes that cooperate in the pathogenesis of MM and to delineate markers for early detection of disease and potential molecular targets for therapeutic intervention.
The second major goal of our research is the molecular characterization of AKT2, a gene originally characterized in this laboratory and shown to be amplified/overexpressed in certain human cancers. AKT2 encodes a member of the AKT/protein kinase B family. AKT kinases have been implicated in disparate cell responses, including promotion of genomic instability, cell survival, proliferation, and invasiveness. Investigations are currently focused on elucidating the role of AKT2 in various human cancers, particularly pancreatic and ovarian carcinomas. AKT activation is frequently observed in various human cancers and may occur early in tumor progression. Cancer cells with constitutively active AKT may have a dependence on AKT activity for survival, and inhibition of AKT signaling can sensitize cancer cells to apoptosis induced by chemotherapeutic drugs or radiation. Thus, studies are underway to exploit AKT as a potential biomarker of cancer progression and as a therapeutic target. We have generated several different AKT transgenic mouse models that are predisposed to the development of certain neoplasms. We are using these mice for preclinical studies, in which components of the AKT pathway are used as targets for chemotherapeutic or chemopreventive strategies.