Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 8%. This dismal outlook is largely due to the inability to diagnose PDAC before metastasis occurs. With 52% of patients being diagnosed at metastatic stage, there is a critical need to better understand the mechanisms of metastatic progression in this disease. One hallmark of PDAC is inflammation. While many studies have focused on elucidating the mechanisms by which inflammation drives PDAC progression, few have focused on the role inflammation plays in metastasis. Using a novel inflammation-driven mouse model of PDAC, a subset of genes was uncovered that not only were regulated by increased inflammation, but also correlated with poor PDAC patient prognosis. The overall goal of this research was to investigate the role and regulation of one of the genes found in this subset that is involved in metastatic progression, namely, metastasis suppressor protein 1 (MTSS1). It was established that loss of MTSS1 leads to increased invasion and migration in PDAC cells. Moreover, cells treated with cancer-associated fibroblast-conditioned media also have increased metastatic potential, which is augmented by MTSS1 loss. Additionally, overexpression of MTSS1 in PDAC cells leads to a loss of migratory potential in vitro and an increase in overall survival in vivo. Furthermore, a novel regulatory mechanism for the stabilization of MTSS1 via the tumor suppressor protein, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was discovered. The data show that PTEN loss results in increased metastatic potential and decreased MTSS1 expression in vitro. Furthermore, it was found that ectopic MTSS1 expression rescues this effect. Additionally, it was demonstrated that PTEN forms a complex with MTSS1, stabilizing it from proteasomal degradation. Finally, it was shown that the inflammatory tumor microenvironment, which makes up over 90% of PDAC tumor bulk, is capable of downregulating PTEN expression, potentially uncovering a novel extrinsic mechanism of MTSS1 regulation. Collectively, these data offer both new insight into the role and regulation of MTSS1 in suppressing tumor cell invasion and migration as well as a different glimpse as to what molecular mechanisms could be leading to early cell dissemination in PDAC.
Investigating the Role of MTSS1 in the Metastatic Progression of Pancreatic CancerDoctoral Dissertation
|Author||Ann E. Zeleniak|
|Contributor||Reginald Hill, Research Director|
|Degree Level||Doctoral Dissertation|
|Degree Discipline||Biological Sciences|
|Degree Discipline||Integrated Biomedical Sciences|
|Departments and Units|