Influence of the microenvironment on development of pancreatic cancer with Anna L. Means
Work in my lab investigates signaling pathways that regulate cell-cell interactions during development of pancreatic cancer. In particular, we are interested in how the epidermal growth factor receptor (EGFR) and one of its ligands, heparin-binding epidermal growth factor-like growth factor (HB-EGF), coordinately regulate both epithelial tumorigenesis and the fibrosis that forms the microenvironment surrounding the developing tumor. We have found that the initiation of pancreatic cancer does not follow the classic paradigm seen in colon cancer where loss of a tumor suppressor gene initiates tumorigenesis and then acquisition of an oncogene promotes tumor formation. The pancreas seems to require two oncogenic events to initiate and promote tumorigenesis with tumor suppressors acting later to increase progression to malignant disease. In the mouse models we have designed, the two oncogenes that are sufficient to initiate and promote pancreatic cancer are KrasG12D and elevated expression of HB-EGF. We are currently understanding how these two oncogenes synergize at the molecular level. We are also investigating targeting the normal source of HB-EGF, inflammatory cells, to determine whether HB-EGF alone or in concert with other cytokines produced by inflammatory cells is necessary for tumor formation.
In a related line of investigation, we have found that overexpression of HB-EGF also increases fibrosis in the pancreas. Fibrosis is a consistent character in pancreatic cancer and likely provides the signals necessary for survival and growth of the tumor and well as providing a barrier to chemotherapeutic treatment. We are using mouse models in conjunction with human tissue analysis to understand how this fibrosis arises and how it can be altered to allow access of chemotherapeutic agents to the tumor.
We have found that epithelium and mesenchyme/stroma are also coordinately regulated during embryonic development. Understanding how interactions between these tissues are regulated will indicate pathways that may also function in those interactions that occur during tumorigenesis in the adult. During embryonic development, mesenchyme (embryonic stroma) is critical for pancreatic development even though only the epithelium gives rise to the pancreas. Removal of surrounding mesenchyme prevents growth and alters the differentiation profile of the pancreatic epithelium. We have found that blocking EGFR signaling has a similar effect to removing the surrounding mesenchyme -- growth is severely compromised and differentiation is altered. We have localized EGFR protein at the epithelial-mesenchymal interface, supporting our hypothesis that EGFR signaling mediates the crosstalk between these two tissues.
All of this work uses a variety of experimental approaches. We use transgenes and gene knockouts to study regulatory processes in vivo. Whenever possible, we correlate our findings back to human pancreatic cancer tissues. We also do culture of cells and tissues isolated from mice to manipulate signaling events in controlled, measurable ways. We use physiology, histology, and molecular biology to understand development and disease on a holistic basis, all the way from the individual to the organ to the tissue and finally to the molecules within cells.