Matt Topham and Diana Stafforini have worked together on various projects since 1994 and jointly lead their laboratory on the third floor of Huntsman Cancer Institute. The current focus of the laboratory is to elucidate molecular events that contribute to the pathogenesis of colon, lung and prostate cancer, with a central focus on inflammatory and tumorigenic events elicited by lipid mediators. The goal is to utilize this information to target key inflammatory and growth pathways in these epithelial malignancies. These researchers utilize an experimental approach that is interdisciplinary and includes molecular and biochemical studies in cellular and animal models. The team is highly collaborative and wishes to develop translational projects of interest to the Huntsman Cancer Institute community as well as external collaborators.
1. Inflammatory events in colon tumorigenesis
One of the areas of interest in the Topham-Stafforini laboratory is to investigate the role of inflammation in colon carcinogenesis. To accomplish this, Topham and Stafforini teamed up with colleagues at HCI (Drs. Jones, Angus-Hill, and others) to develop a unified project that has basic science, translational and therapeutic components. Topham and Stafforini lead one of four projects under the umbrella of a Program Project Grant funded for five years by the National Cancer Institute. The project led by Drs. Topham and Stafforini is based on their long-standing work in the field of inflammation.
Colon cancer often arises following years of low grade, but constant, intestinal inflammation. Understanding how this response contributes to colon carcinogenesis is important from several standpoints. First, it will improve our ability to prevent or minimize the development of this disease through adjustments in lifestyle. Second, the work will increase our understanding of the molecular pathways that contribute to the onset and development of colon cancer. Third, the results may lead to development of pharmacological strategies to manage and treat colon cancer patients.
Topham and Stafforini are investigating novel connections between inflammation and Adenomatous polyposis coli (APC), a tumor suppressor gene whose mutation predisposes to colon cancer. Previous work led by Dr. David Jones showed that APC controls the synthesis of retinoic acid (RA, vitamin A). Joint work by the Jones and the Topham-Stafforini laboratories established that RA is a negative regulator of an inflammatory enzyme (cyclooxygenase-2, COX-2) that contributes to faster development of colon cancer. This collaborative effort identified a molecular mechanism that explained, in part, why blocking COX-2 is a useful approach to prevent and treat colon cancer. In related work, the team established that COX-2 contributes to the progression of colon cancer in animal models, and that signaling through this axis is also enhanced by activation of the epidermal growth factor (EGF) receptor (EGFR). A portion of their work constitutes, in part, the basis for an ongoing clinical trial aimed at preventing tumor development in subjects harboring mutations in the APC gene. More recently, the team has been focusing its efforts on the characterization of additional colon cancer pathways known to be directly or indirectly involved in inflammation. These include molecular events mediated by the phospholipase A2 PLA2G7 and by a functionally-related G protein-coupled receptor. The investigators are currently identifying new pathway intermediates involved in the progression of colon cancer, with the goal of utilizing this information in the development of targeted therapeutic approaches.
2. Regulation of inflammatory lipid signaling in prostate tumorigenesis
Prostate cancer (CaP) is the third leading cause of death among American men. Mortality results from progression from androgen-dependent to androgen-independent disease and from the development of metastases to bones and lymph nodes. To achieve this, tumors release factors that attract and activate cells normally associated with inflammatory processes. This project capitalizes on our expertise in the characterization of signals necessary to turn inflammation “on” and “off.” Inflammation is an essential, normal mechanism that our bodies utilize to fight infections and to recover from certain forms of injury. However, sometimes our bodies over-react and fail to regulate inflammation, a feature that can lead to the onset and development of CaP. We have found that in human CaP many of the proteins that regulate inflammation are present at levels that differ from those observed in healthy prostate tissues. We have focused our work on PLA2G7 and the pathways controlled by this enzyme, with the goal of elucidating their contribution to severe forms of CaP. Our long-term objective is to explore whether blocking inflammation mediated by PLA2G7-regulated events has beneficial effects in CaP, using mice and cellular models as experimental systems.
3. EGFR-mediated control of lung cancer
With over 1 million deaths each year, lung cancer is the leading cause of cancer deaths worldwide. Much of this disease is due to tobacco smoking, but globally up to 25% of all lung cancers occur in never smokers. Often, lung cancers in never smokers harbor specific mutations in genes that are important for tumor maintenance and growth. These oncogenic mutations can sustain tumorigenesis and are, thus, ideal targets for cancer therapy. One gene that is mutated in almost 60% of lung cancers in never smokers is the epidermal growth factor receptor (EGFR). In many cases, these mutations in EGFR cause the tumor to become “addicted” to its tumor promoting properties. As such, about 75% of lung tumors harboring mutant EGFR respond to small molecule EGFR kinase inhibitors. Unfortunately, most patients who initially respond to EGFR inhibitors eventually develop resistance to them by a variety of mechanisms and their tumors begin to grow again. This has led to additional efforts to identify mechanisms of resistance or find other signaling pathways that are important for tumorigenesis promoted by mutant EGFR. We are using a mouse model of mutant EGFR lung cancer to identify inflammatory mediators that could be targeted for treatment. These experiments could provide novel approaches to treat EGFR mutant lung cancer.
4. Diacylglycerol Kinases in the Control of Cell Growth
An additional focus of interest in lipid-based signaling in the Topham-Stafforini laboratory is the examination of the fate of the intracellular messenger diacylglycerol (DAG). DAG accumulates transiently in cells exposed to growth factors or other stimuli. Elevated DAG mediates diverse cellular responses such as growth and differentiation by virtue of binding to and activating protein kinase C. This process can be activated inappropriately in cancer cells, as these cells often have high levels of diacylglycerol. Dr. Topham has provided key insights into the regulation of this process by identifying and cloning several genes that encode diacylglycerol kinases, enzymes that shut off the DAG activation signal. Moreover, he has shown that one of the DGK isoforms has a novel mechanism for shuttling in and out of the nucleus and that while in the nucleus it suppresses growth signals. This biologic mechanism is relevant to many types of cancer. The discovery of this large family of lipid kinases has opened many new studies of signaling mechanisms and their cellular consequences, and it is likely that inhibiting a number of these kinases will affect signaling events important for tumorigenesis.