Type

Text

Type

Dissertation

Advisor

Ken-Ichi Takemaru | Howard C. Crawford. Ken-Ichi Takemaru. | Wei-Xing Zong | Bernadette Holdener.

Date

2011-08-01

Keywords

Cellular biology -- Oncology | ADAM, EGFR, metaplasia, Notch, pancreatic cancer, pancreatitis

Department

Department of Molecular and Cellular Pharmacology

Language

en_US

Source

This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.

Identifier

http://hdl.handle.net/11401/70794

Publisher

The Graduate School, Stony Brook University: Stony Brook, NY.

Format

application/pdf

Abstract

The almost universal lethality of pancreatic ductal adenocarcinoma (PDA) has led to intense study to identify the genetic mutations and molecular abnormalities responsible for its formation and progression. The initiation of PDA is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that universal pancreatic expression of mutant KRas alone is insufficient to initiate tumorigenesis, and requires secondary events, such as tissue damage or changes in molecular signaling pathways, to augment its transformation potential. Our lab studies how chronic inflammation, with or without oncogenic KRas, contributes to tumor formation by the epithelial changes it induces and the molecular mechanisms it changes. My research focuses specifically on ADAM-mediated signaling, specifically how ADAM17 and ADAM10 contribute to pancreatic tumorigenesis and progression, respectively. ADAMs (A Disintegrin And Metalloproteinases) are a class of membrane-tethered metalloproteinases whose misexpression and/or dysregulation has been implicated in many diseases, including cancer. With the use of pancreas-specific ADAM17 conditional knockout mice, we have discovered that the loss of ADAM17 blocks acinar-to-ductal metaplasia, a possible preneoplastic precursor lesion seen in chronic pancreatitis patients. Moreover, we have shown that the loss of ADAM17 also blocks tumorigenesis, with or without pancreatitis induction, possibly due to the blockade in metaplastic duct formation. ADAM17 is well known for shedding Epidermal Growth Factor Receptor (EGFR) ligands, and so by demonstrating the loss of EGFR activation in vitro and in vivo, we have shown that ADAM17-mediated EGFR signaling is necessary for these premalignant changes to occur. Verifying this finding in vivo using a pancreas-specific EGFR conditional knockout mouse, we have shown that pancreatic tumorigenesis, with or without pancreatitis induction, requires stimulation of the endogenous EGFR, most likely by the activity of EGFR ligand sheddase, ADAM17. Furthermore, loss of the EGFR results in less efficient and sustainable ERK/MAPK signaling, yielding less proliferative, and possibly less transformation-sensitive acinar cells. Additionally, we created a pancreas-specific ADAM10 conditional knockout mouse, and discovered that the loss of ADAM10 prolongs survival time by slowing tumor and malignant progression, possibly due to attenuation in active Notch signaling. Altogether, these studies have shown that ADAM17-EGFR signaling is necessary for mutant KRas-driven pancreatic tumorigeneis, while ADAM10-Notch signaling is necessary to promote mutant KRas-driven malignant progression.

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