Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC.

Keywords: Acinar cells; Acinar-to-ductal metaplasia; Pancreatic ductal adenocarcinoma; Reprogramming; Signal transduction.

Figure 1

MAPK, Wnt, Notch and PI3K/Akt signaling is involved in acinar-to-ductal metaplasia. The potential therapies are shown in red (retinoic acid is not shown). EGF: Epidermal growth factor; TGFα: Transforming growth factor alpha; MMP7: Matrix metalloproteinase 7.

Figure 2

Development of pancreatic intraepithelial neoplasia pancreatic ductal adenocarcinoma from acinar cells through acinar-to-ductal metaplasia. During ADM, cells in each state have their own morphology and protein expression pattern. ADM: Acinar-to-ductal metaplasia.