RT Journal Article
SR Electronic
T1 HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 238097
DO 10.1101/238097
A1 Ethan V. Abel
A1 Masashi Goto
A1 Brian Magnuson
A1 Saji Abraham
A1 Nikita Ramanathan
A1 Emily Hotaling
A1 Anthony A. Alaniz
A1 Chandan Kumar-Sinha
A1 Michele L. Dziubinski
A1 Sumithra Urs
A1 Lidong Wang
A1 Jiaqi Shi
A1 Meghna Waghray
A1 Mats Ljungman
A1 Howard C. Crawford
A1 Diane M. Simeone
YR 2017
UL http://biorxiv.org/content/early/2017/12/21/238097.abstract
AB The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, PCSC depletion, and downregulation of OCT4 expression. Conversely, HNF1A overexpression increased PCSC numbers and tumorsphere formation in pancreatic cancer cells and drove PDA cell growth. Importantly, depletion of HNF1A in primary tumor xenografts impaired tumor growth and depleted PCSCs in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of the PCSC state and novel oncogene in pancreatic ductal adenocarcinoma.