Simeone Lab Projects:
Stem CellsEmerging evidence suggests that malignant tumors are composed of a small subset of distinct cancer cells, termed "cancer stem cells" (typically less than 5% of total cancer cells based on cell surface marker expression), which have great proliferative potential, as well as more differentiated cancer cells, which have very limited proliferative potential. Data have been provided to support the existence of cancer stem cells in several different types of cancer, including human blood, brain, prostate, ovarian, melanoma, colon, and breast cancers. We have recently reported the identification of a subpopulation of pancreatic cancer cells that express the cell surface markers CD44+CD24+ESA+ (0.2-0.8% of all human pancreatic cancer cells) that function as pancreatic cancer stem cells. The CD44+CD24+ESA+ pancreatic cancer cells are highly tumorigenic and possess the stem cell-like properties of self-renewal and the ability to produce differentiated progeny. Pancreatic cancer stem cells also demonstrate upregulation of molecules important in developmental signaling pathways, including sonic hedgehog and the polycomb gene family member Bmi-1. Of clinical importance, cancer stem cells in several tumor types have shown resistance to standard therapies and may play a role in treatment failure or disease recurrence. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.
The Simeone lab is also studying a subset of pancreatic cancer cells known as pancreatic cancer stem cells which are responsible for tumor formation, metastasis, and resistance of pancreatic cancer to conventional therapies. More specifically, our lab is assessing the role of genes that are preferentially expressed in pancreatic cancer stem cells versus non-tumorigenic bulk tumor cells. The aim of this research is to determine which of these genes are essential for pancreatic cancer stem cell maintenance, as well as whether targeting these genes can block tumor formation and/or sensitize cells to chemotherapy and radiation. Work is currently underway to establish a pancreatic cancer stem cell signature that might be used as a biomarker to predict patient outcomes and uncover novel therapeutic targets in pancreatic cancer.
An additional project is focused on studying the extensive desmoplasia found in pancreatic cancer. Carcinoma cells live in this complex microenvironment comprising of ECM, diffusible growth factors, cytokines and a variety of non-epithelial cell types including immune cells, fibroblasts and stellate cells. While the use of therapeutics that target the stroma is emerging, the precise role of stroma in pancreatic tumorigenesis remains poorly understood. In the Simeone laboratory we have been focusing on understanding the role of tumor microenvironment in cancer initiation, progression and metastasis. In particular, we are focusing on the heterogeneous cell populations in the fibro-inflammatory tumor stroma, the mesenchymal stem cells. Work is currently underway to identify and functionaly characterize pancreatic cancer associated mesenchymal stem cells in an attempt to disrupt their interactions with tumor cells which might provide new therapeutic avenues in pancreatic cancer.