GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant <i>Kras</i> -driven pancreatic tumorigenesis in mice

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of <i>Pdx1-Cre;Kras</i>^{<i>G12D/+</i>}<i>;p53</i>^<i>f/+</i> (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type <i>Grp78</i> showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a <i>Grp78</i>^<i>f/+</i> allele (PKC78^f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78^f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of <i>Grp78</i> (<i>c78</i>^<i>f/+</i> ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78^f/+ and <i>c78</i>^<i>f/+</i> pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.