Medical School or Training
Duke University, 1988
University of Michigan Health System, Surgery General, MI, 1995
Our lab is focused on trying to understand the molecular events important in pancreatic tumorigenesis. We are committed to identifying new therapies to improve survival in patients with pancreatic cancer. We have three major projects in the lab:
1) Pancreatic cancer stem cells. Our group was the first to identify a highly tumorigenic subpopulation of pancreatic cancer cells that possess stem cell-like properties. These cells, which have the cell surface marker expression CD44+, CD24+, ESA+, account for approximately .5-1% of all human pancreatic cancer cells and have the ability to self-renew and generate the phenotypic heterogeneity of the primary tumor. We are currently studying the optimal marker(s) to identify human pancreatic cancer stem cells that can be used to measure cancer stem cell burden in human biopsy samples, determining therapeutic approaches to specifically target pancreatic cancer stem cells, and define the mechanisms by which these cells are resistant to standard therapies. http://www.cancer.med.umich.edu/pancreatic-cancer-research/simeone-lab-projects.shtml
2) Understanding the role of ATDC in human pancreatic cancer. We have recently found that the majority of human pancreatic adenocarcinomas over-express the gene for Ataxia-Telangiectasia Group D Associated (ATDC). The ATDC gene was initially described in association with the genetic disorder ataxia-telangiectasia (AT) but was later found not to be the gene responsible for AT. We have identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells when exposed to DNA damaging agents such as ionizing radiation and gemcitabine. We have shown that following DNA damage, ATDC traffics to the nucleus, is phosphorylated and localizes to DNA damage repair foci. Loss of ATDC results in increased sensitivity to gemcitabine- and radiation-induced apoptosis and a defect in downstream cell cycle checkpoint signaling. We have also found that high levels of ATDC confer a growth advantage to pancreatic cancer cells both in vitro and in vivo. The ATDC-mediated stimulation of cell proliferation may be due to enhancement of the β-catenin pathway since overexpression of ATDC increases β-catenin-mediated transcription. ATDC interacts with the HIT family protein HINT1, which is a negative regulator of the β-catenin pathway, and we hypothesize that ATDC stimulates β-catenin-mediated proliferation by sequestering HINT1. We are currently investigating the molecular mechanisms by which ATDC functions in the promotion of growth of pancreatic cancer cells as well as its role in the DNA damage response and resistance to standard therapies.
3) Investigating the role of TGFβ/Smad signaling in pancreatic growth regulation and tumorigenesis. TGFβ is an important regulator of growth inhibition in the pancreas and loss of this growth inhibitory function contributes to pancreatic tumorigenesis. We have recently reported an important crosstalk mechanism by which that TGFβ activates protein kinase A (PKA) by a cAMP-independent mechanism through Smad proteins. This interaction requires the formation of a trimeric complex between an activated Smad3/Smad4 complex and the regulatory subunit (R) of the PKA holoenzyme. We have defined the interaction domains of these 3 proteins and have discovered that PKA activation through interaction with Smads is critical in the regulation of many TGFβ-mediated responses. We are currently testing if PKA regulates nucleocytoplasmic trafficking of Smads, and through this mechanism mediates TGFβ-regulated growth responses in pancreatic cells.
Diane M. Simeone, M.D. is the Lazar J. Greenfield Professor of Surgery in the Section of General Surgery, Division of Gastrointestinal Surgery and Associate Professor of Molecular and Integrative Physiology. Dr. Simeone received her bachelor's degree from Brown University in Providence, Rhode Island and a medical degree from Duke University Medical School in Durham, North Carolina. She completed her General Surgery residency training in 1995 at the University of Michigan Medical Center. She joined the faculty at the University of Michigan Medical Center in 1995. Dr. Simeone's clinical interests are in the area of gastrointestinal oncology. She has a special interest in the surgical treatment of pancreatic adenocarcinoma, and is the Surgical Director of the Multidisciplinary Pancreatic Cancer Clinic. Dr. Simeone is the principal director of a research laboratory that is funded by the National Institutes of Health. Her basic science laboratory investigates mechanisms of pancreatic growth regulation and molecular events important in the development and progression of pancreatic adenocarcinoma. She is also an associate member of the Early Detection Research Network (EDRN), an NCI-funded initiative to identify and validate early detection biomarkers for the diagnosis of pancreatic cancer.