Mechanisms of Pancreatic Tumor Nerve Invasion

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DESCRIPTION (provided by applicant): The goal for this proposal is to understand human pancreatic tumor cell adhesion, migration and invasion on nerves and to use this information to block aggressive spread of disease beyond the pancreas. The central hypothesis is that laminin dependent nerve invasion during pancreatic cancer metastasis is dependent upon A6B1. Specifically, the role of the laminin binding integrin A6B1 at the molecular and cellular level will be evaluated using both an in vitro tissue culture method and in vivo using a xenograft SCID mouse model. Several key observations have stimulated this work. First, laminin binding integrins drive invasion and metastasis of human pancreatic cancer and they are persistently expressed in human pancreatic cancer and during nerve invasion. The extracellular matrix laminin proteins are essential for normal development and function of the peripheral nervous system through Schwann cell myelination of axons and are present on pancreatic nerves. It has been shown that blocking expression or function of A6B1 curtails invasion and metastasis of tumor cells both in vivo and in vitro. How A6B1 facilitates adhesion and migration on pancreatic nerves with subsequent metastasis and/or recurrent disease has yet to be fully elucidated. Early detection and targeting of A6B1 dependent migration and invasion on nerves may eliminate the clinical reality of late diagnosis and apparent metastatic sites. If proven correct, this hypothesis could have important translational implications. The therapeutic strategy would consist of ablation of the primary lesion using surgery with prophylactic anti-integrin antibodies thereby inhibiting the potential source for metastases. This is a new concept of pancreatic cancer control directed at adhesion dependent nerve invasion. We will test our central hypothesis by three specific aims using a combination of expertise including collaborations between experts in Molecular and Cellular Biology, Pathology and Neuroscience. All aims contain functional endpoints of laminin 511 dependent adhesion and migration using a novel in vitro tissue culture method and in vivo, using an orthotopic pancreatic nerve invasion xenograft model. Understanding the fundamental molecular basis of adhesion dependent sanctuary of tumor cells on nerves and their subsequent invasion beyond the pancreas will lend novel insight into mechanisms controlling pancreatic cancer cell migration and metastasis. PUBLIC HEALTH RELEVANCE: The goal for this proposal is to understand human pancreatic tumor cell adhesion, migration and invasion on nerves and to use this information to inhibit aggressive spread and development of metastases. Specifically, the requirement for laminin dependent adhesion through the receptor A6B1 in directing invasion and metastasis on nerves will be evaluated. If successful, the results of the project will provide a new therapeutic strategy and concept of pancreatic cancer control directed at blocking tumor invasion on nerves.