Our research efforts are currently focused on the following:
Stem CellsThis project is led by the Simeone Laboratory.
Emerging 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.
BioMEMS for Cancer Detection and DiagnosisThis project is led by the Nagrath Laboratory. We are developing microfluidic devices for isolating and studying cancer cells as related to metastasis.
Metastasis occurs when cells disseminate from the primary tumor site(A) and travel through the body's vasculature(B), then exit the vessels into distant tissues(C), adapt to the microenviroment and proliferate into new tumors(D).
We are using microfluidic devices to study cell migration, specifically how cancer cells enter and exit the vasculature, detecting circulating cancer cells in the blood, and studying the microenvironmental cues needed to sustain and grow tumor metastases.
Microfluidic devices allow for studying individual cell behavior, capturing rare cells, such as circulating tumor cells (CTCs), and sustaining cell cultures. Microfluidics are being created to mimic in vivo environments and will become more widely used in biology as the devices become more automated for general use.
Initiation and progression of pancreatic cancer, focusing on signaling pathwaysThis project is led by the Pasca di Magliono Laboratory. Pancreatic cancer develops through a series of precursor lesions known as Pancreatic Intraepithelial Neoplasia or PanINs. PanINs are characterized by the presence of a mutated form of the Kras gene and, in advanced lesions, by loss of tumor suppressor genes. Cell signaling pathways that are important during embryonic development but are normally inactive in most adult cells are reactivated in PanINs and in pancreatic cancer.
The research in the Pasca lab concentrates on the initiation and progression of pancreatic cancer with a focus on signaling pathways, such as Sonic Hedgehog and Wnt, that are aberrantly activated during carcinogenesis. In particular our research focuses on how these signaling pathways mediate the interactions of tumor cells with components of the tumor stroma. Our lab also looks to explore the link between inflammation and pancreatic cancer.
Novel Approaches to Explore Mechanisms of Gene ExpessionThis project is led by the Ljungman Laboratory.
The current work in Dr. Ljungman's laboratory is focused on exploring the mechanisms by which genes are regulated in normal and cancer cells. The group has developed a set of techniques termed, Bru-Seq, BruChase-Seq qnd BruUV-Seq, to explore RNA synthesis and stability, splicing, transcription elongation and the regulation and mapping of enhancer elements. With these technique a much more comprehensive picture of gene expression and regulation can be obtained than with other current technologies. The Ljungman lab is currently using these techniques to explore gene expression signatures in pancreatic cancer cell lines and patient samples as well as in cell lines in which expression of cancer-specific factors have been knockdown with RNAi.
Radiation and Cancer Biology in the PancreasThis project is led by the Morgan Laboratory.
The Morgan lab is focused on improving chemoradiation therapy for pancreatic cancer through the integration of molecularly targeted agents. We specialize in preclinical work in mouse models of human cancer which can be translated to improved clinical trial designs for patients. The Morgan laboratory is currently investigating several targeted agents including those which impair the response of tumor cells to DNA damage as well as increase apoptotic cell death in pancreatic cancer cells. Our long-standing research on inhibitors of the DNA damage response in tumor cells has led to a planned clinical trial combining the Wee1 inhibitor, MK1775 with chemoradiation therapy for patients with locally advanced pancreatic cancer. We are currently working to identify biomarkers that may be used in future clinical trials to predict a patient's response to this new therapy.
This effort is led by the Sebolt-Leopold Laboratory. Blocking KRAS mediated oncogenic signaling
The Sebolt-Leopold lab is focusing on the identification and optimization of molecular targeted approaches to block KRAS mediated oncogenic signaling. Leveraging the drug discovery and cancer biology expertise of our research team, we are focusing on the design of improved treatment strategies specifically directed toward pancreatic and colorectal cancers. Among our research programs is a long standing interest in designing MEK inhibitor-based combination treatment regimens tailored to the molecular signatures of individual tumors. By integrating biologically driven target and agent selection with the establishment of clinically relevant animal models, we hope to exploit biomarker-enabled preclinical pharmacology trials to inform future clinical testing.
Biotechnology - Protein Expression in Cancer CellsThis project is led by the David M. Lubman Research Laboratory.
Protein fucosylation plays an important role in regulation of cell adhesion and has been an important therapy target for cancer and 'inflammation. In our work, we aim to identify protein site-specific core fucosylation changes related to pancreatic cancer. We have incorporated a multiple enzymatic digestion scheme, solid phase enrichment of glycopeptides and state-of-the-art LC-MS/MS techniques, and successfully profiled the core fucosylation sites in mid to low abundance proteins in human serum. Furthermore, we utilized isobaric mass labels and quantified core fucosylation level changes associated with pancreatic cancer and chronic pancreatitis. While most studies focus on the general level of fucosylation changes, our research provides insights in detailed locations of such changes, and is valuable in pancreatic cancer glycoprotein biomarker identification.
This effort is led by the Research in Radiation OncologyLawrence Laboratory.
Since its inception in 1983, the U-M Department of Radiation Oncology has built and maintained its distinguished position as a national leader in providing first-rate cancer care and producing cutting-edge research to advance the effectiveness and success of cancer treatment. Today, under the leadership of director Dr. Theodore Lawrence, Isadore Lampe Professor and chair, the department enjoys a well-earned reputation as an authority in treating cancer patients.
Biology of Pre-Cancerous Lesions of Epithelial OrgansThis project is led by Andrew Rhim, M.D., Assistant Professor of Gastroenterology, Medical School
My research program is focused on the biology of pre-cancerous lesions of epithelial organs and the molecular and cellular events that occur during their transition to cancer. I employ unique genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) as a model for cancer development and progression. The overarching goal of these studies is to learn more about how cancer evolves so that we may devise new strategies for early diagnosis and treatment for patients with clinically occult advanced precancerous lesions and early forms of cancer. Three themes underscore my work:
1). Identifying the key molecular (genomic and transcriptional) events that drive the development and progression of precancerous lesions of the pancreas;
2). Dissecting and contrasting the interactions between the epithelium and the inflammatory stromal compartment during pancreatitis, pre-cancer (PanIN), and cancer development;
3). Understanding the molecular and cellular requirements and clinical implications of blood-borne dissemination and distant organ seeding of pancreatic epithelial cells, an unexpectedly early event during the transition from pre-cancer to cancer in multiple organs (studies involve both murine and human specimens).
We use this information to design novel strategies to treat pancreatic cancer as well as to devise ways to prevent PDAC from forming in at-risk patients. Finally, we are conducting several clinical trials to test the utility of biomarker candidates identified in our mouse models to predict subsequent tumor formation in patients at high-risk for carcinoma and in remission.