The 5-year survival rate for pancreatic cancer patients is only 8%, the lowest of all major cancers. Therefore, we desperately need an increased understanding of pancreatic cancer biology in order to identify new therapeutic targets. During pancreatic oncogenesis, kinases are constitutively activated, and phosphatases, such as Protein Phosphatase 2A (PP2A), are suppressed leading to aberrant activation of signaling pathways that regulate proliferation, survival, and therapeutic resistance. The goal of my research program is to elucidate the role of PP2A in pancreatic tumorigenesis, therapeutic resistance, and cell plasticity.

Project 1: Defining the PP2A-dependent signaling pathways that contribute to cellular plasticity in pancreatic cancer

Expression of oncogenes, such as KRAS, can induce the transdifferentiation of pancreatic acinar cells to a duct-like state in a process called acinar-to-ductal metaplasia (ADM). ADM is dependent on transcriptional gene programs that induce dedifferentiation and support a ductal cell fate, while simultaneously suppressing an acinar cell fate. Importantly, the cellular rewiring that occurs during these early tumor initiating events has been shown to have a significant impact on disease progression and therapeutic resistance. Given that PP2A suppresses several key oncogenic pathways implicated in ADM, we aim to define the mechanisms that regulate PP2A during this process, as well as the contribution of this phosphatase to cellular plasticity.

Project 2: Determine the impact of PP2A suppression on pancreatic cancer progression and metastasis

Human PDA cells feature low levels of PP2A activity coincident with an upregulation of PP2A inhibitors, suggesting that suppression of PP2A may be a common event in PDA. While PP2A is generally thought to function as a tumor suppressor, the regulation and contribution of individual PP2A subunits to tumorigenic phenotypes remains unclear. Using novel mouse models, we aim to determine the impact of PP2A suppression on the development of pancreatic lesions, progression to a malignant state, activation of the tumor microenvironment, and metastasis.

Project 3: Determine if therapeutic activation of PP2A can suppress the epigenetic changes that drive cellular plasticity during PDA initiation and progression

The constitutive activation of kinases significantly impacts pancreatic cell fate, contributing to ADM and altering transcriptional programs. Therapeutic inhibition of epigenetic factors, such as bromodomain-containing proteins and histone deacetylases, can suppress ADM, suggesting that epigenetic rewiring downstream of kinase signaling is essential. The therapeutic activation of PP2A through the use of small molecule activators of PP2A (SMAPs) attenuates oncogenic signaling by suppressing ERK, AKT, mTOR, BCL-2, and c-MYC pathways. Importantly, PP2A has been shown to regulate epigenetic modifiers, such as BRD4, and the knockdown of PP2A increases resistance to BET inhibitors. Given the central role of PP2A in regulating signal transduction, we aim to determine if activation of PP2A leads to epigenetic reprogramming that reverses or attenuates the progression of early pancreatic lesions.