Matthias Hebrok, PhD

Core

My laboratory uses developmental biology tools to decipher the mechanisms that underlie mammalian pancreas organogenesis and pancreatic diseases, including diabetes and pancreatic cancer. In particular, we are focusing on the role of embryonic signaling pathways, including Hedgehog, Wnt, and FGF signaling, during pancreas formation and function. Results from these embryonic studies form the foundation for more translational research aimed to test whether modulation of embryonic signaling pathways permits a) the formation of insulin-producing ?-cells from uncommitted stem cells and b) the prevention of pancreatic tumor formation and growth.

Pancreas Development: Our goal is to decipher the signals that regulate proliferation and differentiation of the distinct pancreatic cell types during pancreas development. We are manipulating embryonic signaling pathways in transgenic mice at different stages of pancreas development via Cre-loxP and tetracycline-inducible systems. These experiments are designed to gain insights into how endocrine and exocrine cell differentiation and proliferation are regulated. In addition, we have developed real time imaging techniques to visualize epithelial branching, progenitor cell expansion, and migration of insulin-producing ?-cells in embryonic organ cultures. We are currently employing these advanced microscopy techniques on transgenic pancreas rudiments to obtain novel information about organ morphogenesis and cell differentiation.

Pancreatic Cancer: Our goal is to understand the molecular mechanisms underlying the formation and growth of pancreatic adenocarcinoma. I anticipate that this knowledge will help to devise new strategies to combat the disease in humans. Pancreatic adenocarcinoma constitute the fourth leading cause of cancer death in the United States. The disease is characterized by rapid progression and early metastatic potential. The absence of specific symptoms in addition to the resistance to chemotherapeutic intervention results in a median survival of less than six months after diagnosis. Our studies have implicated overt Hedgehog signaling both in the formation and maintenance of pancreatic adenocarcinoma. More recently, we have demonstrated synergistic interactions between Hedgehog and Ras signaling during development and progression of neoplastic lesions in the pancreas. Our current efforts focus on the molecular mechanisms by which Hedgehog signaling regulates the formation of neoplastic lesions and how Hedgehog inhibition might be used for therapeutic intervention.

Differentiation of Embryonic Stem Cells towards Functional ß-Cells: Our goal is to generate functional insulin-producing ß-cells from embryonic stem cells by replicating the signaling events during pancreas organogenesis in cell culture. We are testing conditions to optimize the formation of definitive endoderm, the germ layer that gives rise to pancreatic ß-cells, from embryonic stem cells. Our aims are to generate pancreatic endoderm and subsequently ß-cells in cell culture.