The Role and Mechanism of Enhanced Met Expression in Pancreatic Cancer

Pancreatic cancer is the 4th leading cause of cancer deaths in the United States annually and little progress has been made in the past 30 years to improve patient survival. Therefore, it is imperative the signaling pathways that drive pancreatic cancer growth and progression be identified and their mechanisms of action be understood. The HGF/Met signaling axis has been implicated in pancreatic cancer due to increased protein expression of HGF and Met. In this dissertation, I tested the hypothesis that Met signaling promotes pancreatic tumor growth using shRNA mediated knock down of Met in two pancreatic adenocarcinoma cell lines. I showed that cells with reduced Met protein exhibited reduced growth in soft agar, cell motility and tumor growth in vivo; supporting the conclusion that the HGF/Met signaling axis functions to drive pancreatic tumor growth. Not only is it important to understand the role of Met signaling in pancreatic cancer, but also it is imperative that the mechanism resulting in increased Met protein expression be identified in order to effectively target the HGF/Met signaling axis therapeutically. Therefore, I also tested the hypothesis that Met protein levels are posttranslationally regulated in a subset of pancreatic cancers; specifically, that Met down regulation is delayed. My studies demonstrate that Met down regulation is delayed in a number of pancreatic cancer cell lines and that at least two separate mechanisms are responsible. In one cell line, following internalization Met traffics from the early to the late endosome; however, it is not efficiently degraded. In another cell line, impaired Met ubiquitination correlates with Met recycling back to the cell surface. As a whole, the data in this dissertation indicates that the HGF/Met signaling axis regulates pancreatic cancer growth through increased Met protein expression due to impaired Met down regulation. Therefore, the development of therapies that enhance protein degradation or block HGF mediated Met activation could be clinically beneficial for pancreatic cancer patients.

Name thesis:degree_name

Cell Biology (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Cell Biology

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Hill, Kristen S 1982-

Advisor dc:contributor.advisor

• Hellmich, Mark R

Committee members dc:contributor.committeemember

• Elferink, Lisa A
• Sastry, Sarita K
• Davey, Robert A
• Bogler, Oliver

• Pancreatic cancer
• Met
• HGF
• Intracellular trafficking
• receptor down regulation

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/782

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/782