Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment

Abstract

Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults, acinar cells undergo a dedifferentiation process termed acinar–ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix‐loop‐helix (bHLH) factors MIST1 and PTF1a coordinate an acinar‐specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process. However, when MIST1 and PTF1a gene expression is silenced, cells are more prone to progress to PDAC. In this study, we tested whether induced MIST1 or PTF1a expression in PDAC cells could (i) re‐establish the transcriptional program of differentiated acinar cells and (ii) simultaneously reduce tumor cell properties. As predicted, PTF1a induced gene expression of digestive enzymes and acinar‐specific transcription factors, while MIST1 induced gene expression of vesicle trafficking molecules as well as activation of unfolded protein response components, all of which are essential to handle the high protein production load that is characteristic of acinar cells. Importantly, induction of PTF1a in PDAC also influenced cancer‐associated properties, leading to a decrease in cell proliferation, cancer stem cell numbers, and repression of key ATP‐binding cassette efflux transporters resulting in heightened sensitivity to gemcitabine. Thus, activation of pancreatic bHLH transcription factors rescues the acinar gene program and decreases tumorigenic properties in pancreatic cancer cells, offering unique opportunities to develop novel therapeutic intervention strategies for this deadly disease.

Prevention and Reversion of Pancreatic Tumorigenesis through a Differentiation-Based Mechanism

“…While this work was in progress, an independent study demonstrated that overexpression of Ptf1a in Panc1 cells could induce acinar-specific gene expression as well as inhibit clonogenic growth (Jakubison et al, 2018), whereas we find Panc1 to be Ptf1a resistant. The precise reason for this discrepancy is not known, but some differences in methodologies exist.…”

“…The precise reason for this discrepancy is not known, but some differences in methodologies exist. For example, the approach of Jakubison et al (2018) may have achieved higher-level expression of Ptf1a, overcoming an inhibitory threshold not matched by our expression system. In addition, whereas we introduced Ptf1a via polyclonal lentiviral transduction, Jakubison et al (2018) employed stable plasmid transfection and clonal selection.…”

A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma

“…In contrast, mKIC cells exhibit an exclusive mesenchymal phenotype that is characterized by a fibroblastic morphology and high levels of Snail, MMP9 , and fibronectin ( FN1 ) expression. All these cancer cell lines are highly tumorigenic in orthotopic xenograft models …”

Differential Cell Susceptibilities to Kras in the Setting of Obstructive Chronic Pancreatitis

“…Our mouse model of acinar Kras mutation relies on loss of one Ptf1a allele, and this may also contribute to the inability of acinar-derived cells to undergo tumorigenesis. However, work from others indicates that loss of Ptf1a makes acinar cells more susceptible, not less susceptible, to tumorigenesis 33, 34. It is also unlikely that differences in Cre-mediated recombination in our acinar-derived and duct-derived cell models are responsible for the differences in carcinogenesis.…”