Notch signaling in pancreatic cancer: oncogene or tumor suppressor?

Abstract

The Notch signaling pathways are known to play critical roles during pancreatic development, but it remains unclear what functions are important in the adult organ. One area of debate is the role of Notch signaling in the development of pancreatic ductal adenocarcinoma (PDAC) and proposed precursor lesions, pancreatic intraepithelial neoplasia (PanIN). Initial studies revealed that Notch signaling is reactivated during PDAC initiation and development, suggesting that Notch promotes PDAC and may therefore represent a target for drug development. However, more recent work reveals a tumor suppressive role for Notch receptors in the context of PanIN development. Here, we summarize the current literature describing Notch signaling in the development of PDAC, and discuss the potential of the Notch pathway as a therapeutic target.

Figure 1. Gamma-secretase activity is required during activation of the Notch signaling pathway

In mammals, the main components of the Notch pathway include the 4 transmembrane Notch receptors (Notch1–4) and their cognate ligands, Delta-like (DLL) 1, -3, and -4, and Jagged1 and -2. Notch receptors expressed on the cell surface bind to the Delta and Jagged family of ligands on an adjacent cell, after which Notch undergoes a series of proteolytic cleavages. The first cleavage is mediated by either tumor-necrosis factor-α-converting enzyme (TACE) or ADAM10, followed by a second cleavage mediated by the gamma-secretase complex. This final cleavage releases the Notch intracellular domain (NICD) from the cell membrane, allowing this domain to translocate to the nucleus. Once in the nucleus, NICD binds to the transcription factor CSL, displacing corepressors and recruiting transcriptional activators, including the coactivator Mastermind-like1 (Maml). Gamma-secretase inhibitors (GSIs) block the cleavage of Notch receptors by the gamma-secretase complex, inhibiting the release of NICD from the cell membrane.

Figure 2. Notch receptors are expressed in in the mature exocrine pancreas

The mature pancreas is composed of exocrine and endocrine compartments, with the exocrine compartment consisting of acinar, ductal, and centroacinar cells. Notch receptors are known to play critical roles during pancreatic development; however their role and expression patterns in the mature pancreas remain to be fully defined. Genetically engineered mouse models as well as immunohistochemical analysis indicate Notch receptors are expressed and activated in mature exocrine cells.

Figure 3. Mouse models reveal dual roles for Notch receptors

Mouse models reveal that Notch receptors either promote or inhibit PanIN development depending on context. Models differ on the Notch receptor being targeted, timing of genetic events, and the cell types targeted. Additional studies employing gamma secretase inhibitors (GSIs) reveal Notch receptors function to inhibit PanIN advancement early during disease progression and appear to play a minimal role in advanced PDAC stages.