Format

Send to

Choose Destination
Mol Oncol. 2018 Jun;12(7):1104-1124. doi: 10.1002/1878-0261.12314. Epub 2018 May 21.

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

Author information

1
Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
2
Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
3
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
4
Laboratory for Computational Genomics, Indiana University School of Medicine, Indianapolis, IN, USA.
5
Development and Aging Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.

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.

KEYWORDS:

PDAC ; bHLH ; ABC transporters; MIST1; exocrine pancreas; transcription

PMID:
29719936
PMCID:
PMC6026875
DOI:
10.1002/1878-0261.12314
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center