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

• Published in: Molecular oncology 2018-06, Vol.12 (7), p.1104-1124
• Main Authors: Jakubison, Brad L., Schweickert, Patrick G., Moser, Sarah E., Yang, Yi, Gao, Hongyu, Scully, Kathleen, Itkin‐Ansari, Pamela, Liu, Yunlong, Konieczny, Stephen F.
• Format: Article
• Language: English
• Subjects: ABC transporters; Acinar Cells - metabolism; Acinar Cells - pathology; Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animals; Antimitotic agents; Antineoplastic agents; Basic Helix-Loop-Helix Transcription Factors - metabolism; bHLH; Cancer; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; DNA binding proteins; Enzymes; exocrine pancreas; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Gene Silencing; Genes; Genetic aspects; Genetic Loci; Genetic transcription; Mice; MIST1; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Pancreatic cancer; PDAC; Rats; Stem cells; transcription; Transcription Factors - metabolism
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12314

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. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. A key feature of this transformative event is silencing of the proacinar transcription factor genes MIST1 and PTF1a. Here, we show that induction of MIST1 or PTF1a in PDAC can (i) re‐establish the transcriptional program of acinar cells, (ii) reduce tumor cell properties, and (iii) increase efficacy of therapeutic agents.