Project Summary/Abstract
Cellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes
to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high
grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of
metastasizing to distant organs. EMT is a common feature associated with tumor progression and is thought
to be critical to cancer cell dissemination in some tumors, such as pancreatic ductal adenocarcinoma
(PDA). PDA is a lethal and poorly understood human malignancy that is characterized by an activating
mutation in KRAS. Additionally, AXL, a receptor tyrosine kinase (RTK), has been implicated in tumor
progression, metastasis, therapy resistance, and EMT in multiple cancer types including PDA. During my
dissertation studies, I have found that TANK-binding kinase 1 (TBK1), a critical downstream effector of
mutant active KRAS, is central to AXL-driven EMT in KRAS-mutant PDA. However, the mechanism of how
TBK1 drives EMT has yet to be elucidated. We hypothesize that TBK1 drives EMT via activation of AKT3
and the stability of downstream transcriptional networks. My data demonstrate that AKT3 is activated
downstream of TBK1 in response to stimulation of AXL, which leads to the binding of AKT3 and Slug in an
AXL-TBK1 dependent manner. To complete my dissertation, I will establish the function of AKT3 in driving EMT
downstream of Axl and TBK1 with the following goals: 1) Establish the necessity of AKT3 for Axl and TBK1 driven
EMT; 2) Evaluate EMT transcription factors engaged downstream of TBK1 and 3) Determine the effect of AKT3
activation on the stability of EMT transcription factors.
Despite significant evidence that EMT directly contributes to tumor progression, several studies have
suggested EMT is not required for the metastatic spread of PDA and breast cancer. For example, most
metastatic lesions are known to exhibit epithelial features, an observation that seems to be at odds with
EMT as a prerequisite for metastasis. As such, the importance of EMT in cancer biology h as been
questioned. I hypothesize that the chronic activation of an EMT program within a tumor may depend on
paracrine signals within the tumor microenvironment, dictating whether the tumor cells undergo EMT or
MET. Because these cells exist in a plastic state, it is possible that these tumor cells readily revert their
phenotype based on a microenvironment-specific context and factors. Additionally, current in vivo lineage-
tracing technology has not settled the debate between the importance of collective m igration and/or EMT
for metastatic dissemination. During my postdoctoral research, I aim to investigate the role of EMT in
metastasis using in vivo lineage tracing, single-cell sequencing, and organoids to better understand
epithelial plasticity in an oncogene- and tissue-specific manner. Understanding this process will aid in the
development of effective metastatic cancer therapies and will direct future research directions in metastasis.