Examining the Role of Hedgehog Signaling in the Pancreatic Tumor Microenvironment.

Pancreatic Cancer;Hedgehog Pathway;Health Sciences;Cellular & Molecular Biology

Dosch, Joseph ScottMorrison, Sean ;

University of Michigan

关键词: Pancreatic Cancer;    Hedgehog Pathway;    Health Sciences;    Cellular & Molecular Biology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/86276/jdosch_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The Hedgehog (Hh) pathway is a conserved signaling network that plays a critical role during embryonic development as well as in the maintenance of adult tissues.Inappropriate activation of Hh signaling has been linked in the development of several tumors, including pancreatic cancer.In the context of pancreatic cancer, Hh pathway ligands secreted by the tumor cells activate this pathway in the tumor mesenchyme by a paracrine mechanism.As the role of Hh signaling in the tumor mesenchyme is not fully understood, we initiated two strategies to understand how active Hh signaling promotes pancreatic carcinogenesis.In a first approach, we used Hh pathway inhibitors to down-regulate paracrine Hh signaling in an orthotopic xenograft model of human pancreatic adenocarcinoma to test how this pathway is involved in tumor growth and progression.These experiments revealed that blocking Hh signaling in the tumor stroma leads to a significant reduction in the ability of tumor cells to form metastases, along with affecting signals that are important in maintaining the differentiation status of the tumor cells.Second, we established a primary in vitro model of paracrine Hh signaling in pancreatic stellate cells.Using bioinformatics analysis we found that paracrine Hh signaling activates an invasive gene signature in pancreatic stellate cells.This was confirmed by three-dimensional invasion assays in vitro.Several clinical trials for Hh pathway inhibitors, including here at the University of Michigan Medical Center, have been initiated for testing the efficacy of targeting paracrine Hh signaling in the treatment of pancreatic cancer.Our studies established important in vivo and in vitro models to ask important questions about the role of paracrine Hh signaling in pancreatic cancer progression.These studies add insight to how targeting this pathway may provide important therapeutic benefit to pancreatic cancer patients.