Pancreatic ductal adenocarcinoma (PDA) is one of the most devastating cancer-related diseases in the United States. Historically, it was thought these pancreatic tumors arose from the ductal compartment of the tissue based on the morphology of the tumor cells. Recently, this school of thought has been re-evaluated and resounding evidence now points at the acinar cell as the cell of origin. Upon injury, or oncogenic insult, acinar cells undergo a process of acinar-ductal metaplasia (ADM). In the context of tissue injury, such as pancreatitis, ADM is an adaptive response as there is rapid repair of the tissue following cessation of the injury stimulus, a process we have labeled as ?Adaptive? ADM. Interestingly, in the presence of oncogenic signals, such as mutant Kras*, ADM does not recover and instead progresses into precancerous lesions ? the most common being pancreatic intraepithelial neoplasia (PanIN). This progression of ADM under oncogenic stimulus we have labeled as ?Oncogenic? ADM. This proposal will examine the underlying mechanism of how ADM progresses to PanIN in the presence of Kras*, as well as investigate the difference between ?Adaptive? and ?Oncogenic? ADM. Our group has recently identified the paired-related homeobox1 (Prrx1) transcription factor as a potentially important player in ADM. We have previously shown that Prrx1 expression increases during pancreatitis, and that Prrx1 directly interacts with Sox9, a ductal gene important in the formation of ADM and progression to PanIN. Therefore, we hypothesize up-regulation of Prrx1 following pancreatic injury (pancreatitis) results in the maintenance of ADM and allows for subsequent transformation by oncogenic Kras*, thereby promoting pancreatic tumorigenesis. We will test this hypothesis through two interrelated Specific Aims.
Aim 1 will determine the requirement of Prrx1 for the formation and maintenance of ADM and PanIN lesions following pancreatic injury. We will use tissue-specific knockout of Prrx1 (Ptf1aCre;Prrx1f/f) in vivo to determine the requirement of Prrx1 in the formation and maintenance of ADM following caerulein-induced pancreatitis. Additionally, we will knockout Prrx1 in the context of inducible oncogenic Kras* signaling (iKras*;Prrx1f/f). With this model, we can address whether Prrx1 is required for PanIN formation and whether ADM cells lacking Prrx1 are more resistant to transformation by Kras*.
Aim 2 will investigate the regulation of ?Adaptive? and ?Oncogenic? ADM. Using 2D and 3D in vitro assays and tissue from Aim1, we will investigate the mechanisms of Prrx1 regulation by pro-inflammatory cytokines and/or oncogenic Kras* during ?Adaptive? and ?Oncogenic? ADM, respectively. Furthermore, we will take an unbiased approach to identify additional regulation of ?Adaptive? and ?Oncogenic? ADM by isolating ADM cells from iKras* animals following pancreatitis and performing RNAseq to examine differential gene expression. Taken together, these studies will provide new insights into the mechanisms underlying ADM and elucidate what promotes the initiation of pancreatic tumorigenesis instead of tissue recovery.

Public Health Relevance

Pancreatic ductal adenocarcinoma (PDA) is currently the fourth leading cause of cancer-related deaths in the United States, and it is predicted that this will increase to second by the year 2030. The proposed study will investigate the mechanisms underlying the initiating steps of pancreatic tumorigenesis. Results will yield new therapeutic targets or biomarkers for PDA.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA210387-01
Application #
9188974
Study Section
Special Emphasis Panel (ZRG1-F09A-D (20)L)
Program Officer
Mcguirl, Michele
Project Start
2016-07-07
Project End
2019-07-06
Budget Start
2016-07-07
Budget End
2017-07-06
Support Year
1
Fiscal Year
2016
Total Cost
$56,118
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104