Pancreatic ductal adenocarcinoma (PDA) is a devastating disease for which there is no effective treatment. Understanding the biology of PDA formation and maintenance is important for designing treatments for PDA patients. Chronic pancreatitis is a painful disease on its own and is a risk factor for PDA. Both PDA and chronic pancreatitis share many pathological qualities, including a robust inflammatory response, extensive fibrosis and epithelial morphogenesis.
The laboratory of Howard C. Crawford, Ph.D., focuses on the signal transduction pathways that control the common pathologies of these diseases. Dr. Crawford's laboratory has recently found that members of the ADAM family of membrane-bound metalloproteinases control pancreatic tumorigenesis and progression.
Using a combination of animal and cell-based models, the lab found that ADAM17 is required for pancreatic tumorigenesis by shedding epidermal growth factor receptor (EGFR) ligands and activating EGFR, even when these tumors possess oncogenic Kras mutations.
In contrast, ADAM10 modulates PDA progression by activating the Notch receptors, which influences the cancer stem cell properties of metastases.
- Utilize pharmacological inhibitors of the critical components of the ADAM17-EGFR-MEK-CyclinD1 pathway to treat mouse models of PDA to test the necessity of these molecules for tumor initiation and maintenance
- Identify the specific pathways required for the maintenance of cancer stem cells controlled by ADAM10
- Use our knowledge of the necessary in vivo pathways to develop refined mouse models of chronic pancreatitis-induced pancreatic cancer that accurately mimic the human diseases and mine them for new drug targets and disease markers
Significance to patient care
A huge outstanding issue with pancreatic cancer is early detection. Molecular markers for early-stage tumors are very likely to be targets of these essential signaling pathways. Furthermore, by understanding the specific molecular pathways that control pancreatic tumor formation and metastasis, Dr. Crawford and his colleagues can more accurately identify rational drug targets customized for a patient's specific cancer.