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Pancreatic ductal adenocarcinoma (PDA) and chronic pancreatitis are characterized by a dense collagen-rich desmoplastic reaction. Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagens that can regulate cell proliferation, migration, adhesion, and remodeling of the extracellular matrix. To address the role of DDR1 in PDA, Ddr1-null (Ddr-/-) mice were crossed with the KrasG12D/+; Trp53R172H/+; Ptf1aCre/+ (KPC) model of metastatic PDA. Ddr1-/-; KPC mice progress to differentiated PDA but resist progression to poorly differentiated cancer compared with KPC control mice. Strikingly, severe pancreatic atrophy accompanied tumor progression in Ddr1-/-; KPC mice. To further explore the effects of Ddr1 ablation, Ddr1-/- mice were crossed with the KrasG12D/+; Ptf1aCre/+ neoplasia model and subjected to cerulein-induced experimental pancreatitis. Similar to KPC mice, tissue atrophy was a hallmark of both neoplasia and pancreatitis models in the absence of Ddr1. Compared with controls, Ddr1-/- models had increased acinar cell dropout and reduced proliferation with no difference in apoptotic cell death between control and Ddr1-/- animals. In most models, organ atrophy was accompanied by increased fibrillar collagen deposition, suggesting a compensatory response in the absence of this collagen receptor. Overall, these data suggest that DDR1 regulates tissue homeostasis in the neoplastic and injured pancreas.

Background & Aims Mitogen-activated protein kinase (MAPK) signaling in the exocrine pancreas has been extensively studied in the context of pancreatic cancer, where its potential as a therapeutic target is limited by acquired drug resistance. However, its role in pancreatitis is less understood. We investigated the role of mitogen-activated protein kinase kinase (MEK)-initiated MAPK signaling in pancreatitis to determine the potential for MEK inhibition in treating pancreatitis patients. Methods To examine the role of MEK signaling in pancreatitis, we used both genetic and pharmacologic approaches to inhibit the MAPK signaling pathway in a murine model of cerulein-induced pancreatitis. We generated mice harboring inducible short hairpins targeting the MEK isoforms Map2k1 and/or Map2k2 specifically in the pancreatic epithelium. We also used the MEK inhibitor trametinib to determine the efficacy of systemic inhibition in mice with pancreatitis. Results We demonstrated an essential role for MEK signaling in the initiation of pancreatitis. We showed that both systemic and parenchyma-specific MEK inhibition in established pancreatitis induces epithelial differentiation and stromal remodeling. However, systemic MEK inhibition also leads to a loss of the proliferative capacity of the pancreas, preventing the restoration of organ mass. Conclusions MEK activity is required for the initiation and maintenance of pancreatitis. MEK inhibition may be useful in the treatment of chronic pancreatitis to interrupt the vicious cycle of destruction and repair but at the expense of organ regeneration., Graphical abstract

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive and devastating cancer often characterized by an intense collagen-rich, fibrotic response. In the presence of an oncogenic Kras mutation, the pancreas undergoes an initial morphological event in which normal acinar cells transdifferentiate into a ductal-like phenotype in a process called acinar-ductal metaplasia (ADM). ADM advances into pre-cancerous lesions, followed by a subsequent replacement of epithelium with a collagen-dense stromal reaction as PDA progresses. Discoidin domain receptors, DDR1 and DDR2, are a unique family of tyrosine receptor kinases that bind to collagen and activate downstream cellular responses that affect cell proliferation, migration, and adhesion. Our preliminary data shows that during Kras-induced ADM in vitro DDR1 is downregulated and is accompanied by an upregulation of DDR2 expression. Immunohistochemistry on human tissue microarrays reveals DDR1 is expressed in normal epithelia and pre-neoplastic lesions, but downregulated during advanced PDA. Conversely, DDR2 is upregulated in metaplastic lesions and advanced carcinoma as well as in the stroma at all stages of progression, suggesting DDRs may play a differential role throughout the PDA. DDR1 is expressed in epithelial cells and associated with disease states such as fibrosis and various cancers, including PDA. To study the role of DDR1 in pancreatitis, a known risk factor of PDA, we used DDR1-null mice (DDR1-/-) with our cerulein-induced pancreatitis protocol. DDR1 ablation induces tissue damage and impairs recovery from extended cerulein treatment. To understand the role of DDR1 in tumorigenesis, we mated DDR1-/- mice in the KrasG12D/+; Ptf1aCre/+ (KC model) of pancreatic neoplasia. The absence of DDR1 in the KC model does not inhibit nor delay tumorigenesis, however, pancreata are smaller with less differentiated morphology than wild-type KC animals. In contrast, DDR2 is expressed in mesenchymal cells and has been implicated in EMT, cell proliferation, tumor invasion, and required for metastasis in breast cancer, however, its significance in PDA remains unknown. Our preliminary data shows DDR2 co-stains with neuroendocrine positive cells within neoplastic lesions that are associated with poor patient survival. To further investigate the role of DDR2 in tumor progression we have successfully mated a conditional, global DDR2 knockout mouse (DDR2fl/fl; β-actinCreERT2) with our novel KrasFSF-G12D/+;p53FRT/+ ;Ptf1a-FlpO/+ (KPF) aggressive PDA mouse model. Collectively, the results from these studies will help determine the role of DDRs throughout the initiation and progression of PDA and help define a potential point of regulation at the interface between the epithelial-stromal interactions. Citation Format: Jeanine Ruggeri, Christopher Halbrook, Anjum Sohail, Rafael Fridman, Howard Crawford. Determining the role of discoidin domain receptors 1 and 2 in the pathogenesis of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4499.