Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Anil K. Rustgi

Abstract

Pancreatic cancer is the third leading cause of cancer mortality, the overwhelming majority of which is due to metastasis. The mechanisms of dissemination have been intensively studied, but questions remain as to how epithelial properties are regulated between the primary tumor site and destination as well as to how organotropic patterns of metastasis are determined. We demonstrate, using multiple complementary mouse models, that liver and lung metastatic organotropism in pancreatic cancer is dependent on p120catenin (p120ctn)-mediated epithelial identity. Monoallelic p120ctn loss accelerates KrasG12D-driven PanIN/PDAC formation and metastasis to the liver as well as being sufficient for E-CADHERIN-mediated cell adhesion. In contrast, cells with biallelic p120ctn loss demonstrate marked lung organotropism, although rescue with p120ctn restores liver metastasis. In a p120ctn-independent PDAC model, mosaic E-cadherin knockout shows selective pressure for E-cadherin-positive liver metastasis and E-cadherin-negative lung metastasis. Furthermore, human PDAC and liver metastases support the premise that liver metastases exhibit predominantly epithelial characteristics. RNA-seq demonstrates differential induction of pathways associated with metastasis and epithelial-to-mesenchymal transition in p120ctn-deficient versus p120ctn-wild-type cells. Taken together, p120ctn-mediated epithelial plasticity may be added to the list of emerging concepts underlying metastatic organotropism.

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