The role of PP2A B56a in pancreatic tumorigenesis - Project Summary
The majority of pancreatic ductal adenocarcinoma (PDA) patients present with late-stage, metastatic disease
that is often resistant to therapeutics, resulting in extremely low survival rates. Understanding the mechanisms
that regulate the early initiation and progression of PDA is critically important to the development of new, more
accurate pancreatic cancer models for the identification of biomarkers and novel therapeutic targets. Protein
phosphatases are master regulators of cell signaling pathways, including the MAPK and PI3K pathways.
Studies from our lab and others have demonstrated that PDA tumors have increased expression of PP2A
inhibitors and a corresponding decrease in PP2A function, suggesting that the inhibition of PP2A is a common
event in PDA progression. The active PP2A holoenzyme is composed of three proteins including a catalytic
subunit, a scaffolding subunit, and a regulatory (B) subunit that provides target specificity. While PP2A is
thought to function as a tumor suppressor, the individual contribution of specific B subunits to disease
progression is still poorly understood. We have identified the PP2A B subunit, B56, as being an important
regulator of KRAS driven pathways, including the stabilization of the oncoprotein c-MYC. Given that KRAS
mutations occur in 90-95% of PDA patients, regulation of this pathway by B56 represents an important gap in
knowledge. In our preliminary studies, loss of B56 in mice accelerated the formation of pancreatic precursor
lesions and increased the expression of transcription factors involved in cell fate and metastasis. Therefore, I
hypothesize that B56 plays a critical role in mediating pancreatic cell plasticity, and that suppression of B56
will increase the susceptibility of pancreatic cells to oncogenic mutation, driving PDA initiation and
transformation. This hypothesis will be addressed through the following three Specific Aims: 1) Determine the
impact of oncogenic KRAS on PP2A-B56 complex formation and function, 2) Examine whether loss of B56
accelerates the progression of premalignant lesions in vitro and in vivo, and 3) Determine if therapeutic
activation of PP2A-B56 can suppress the transcriptional and epigenetic changes that occur during PDA
initiation. These studies will take advantage of techniques such as single cell epigenetic analysis, mouse
modeling of PDA, and analysis of PP2A composition in human PDA tumors using cyclic immunofluorescence
in order to provide a deep molecular understanding of PDA development in relation to phosphatase function.
Importantly, the transcriptional deregulation of factors involved in cellular plasticity during early tumor
development has been shown to have a significant impact on late stage tumor heterogeneity, subtype, and
therapeutic response. Therefore, results from these studies will provide a strong basis for the future
interrogation of both early and late stage disease, expanding my independent scientific program and
supporting my long-term goal of understanding the molecular basis of PDA.
