Research Interests:
1. E1a. We have found a gene that universally reverses the transformation of human tumor cells, offering an alternative to the formidable challenge of specifically tailoring cancer therapies for each patient’s tumor genotype.

E1a profoundly re-programs tumor cell behavior in vitro and in vivo. First, E1a upregulates epithelial cell adhesion genes, causing a “mesenchymal-to-epithelial transition” – the reverse of epithelial cells’ conversion into carcinoma cells. Secondly, E1a upregulates certain key pro-apoptotic genes. This sensitizes tumor cells to apoptosis in response to detachment from matrix (“anoikis”, see below) as well as death ligands (e.g., TRAIL) and conventional chemotherapeutic drugs/DNA damaging agents. Thus, tumor cells with E1a are viable in culture but become epithelial and anchorage-dependent due to anoikis, thus failing to form tumors.

Several phase I-II clinical trials using E1a gene therapy for breast, ovarian and head/neck cancer have been attempted, but the gene delivery approach is severely limited for cancer. We plan to identify genes or compounds that mimic the p300- or CtBP-inactivating effects of E1a and cause tumor suppression. These will be tested in preclinical and clinical trials for effectiveness against human neoplasia.

2. Anoikis. Our laboratory also discovered the phenomenon of “anoikis”, which is defined as apoptosis that is suppressed by extracellular matrix. Epithelial cells (or tumor cells that have been converted to epithelial cells using E1a) that are released from high-turnover tissues are programmed to undergo anoikis. This response prevents the circulation and colonization of the released cells at inappropriate sites. Conversely, tumor cells must become resistant to anoikis for metastasis to succeed. From the basic research point of view, anoikis conceptually bridges the cell adhesion and the apoptosis fields. Most of the fundamental mechanisms underlying anoikis remain to be discovered, and this will involve the combination of insights into cytoskeletal mechanisms, signal transduction and perhaps specialized apoptotic mechanisms, all of which can be altered by oncogenes or tumor suppressor genes. In a larger sense, anoikis is a new phenotypic difference between epithelial cells and carcinoma cells that offers conceptually novel therapeutic possibilities. The mechanism of anoikis is a major focus of the laboratory.

3. Novel functions of death receptor-related apoptotic factors. We found that an adaptor protein, FADD (FAS-Associated Death Domain protein) for death receptors resides in the nucleus, where it interacts with a MethylCpG-Binding Domain protein (MBD4). Recent data have suggested that this complex may serve to monitor that DNA methylation is complete following replication, and to trigger apoptosis if it is not. We call this novel checkpoint the “methylation checkpoint”. The breakdown of this checkpoint may explain the epigenetic instability of tumor cells – i.e., the tendency of DNA methylation to drift, altering gene expression. This is currently being pursued by genetic and biochemical approaches.

Finally, we found that the direct effector molecule for FADD, caspase-8 has a novel and unexpected function in regulating cell adhesion, motility and cytokinesis. This is being pursued as well.