Objective ARID1A is commonly mutated in pancreatic ductal adenocarcinoma (PDAC), but the functional effects of ARID1A mutations in the pancreas are unclear. Understanding the molecular mechanisms that drive PDAC formation may lead to novel therapies.
Design Concurrent conditional Arid1a deletion and Kras activation mutations were modelled in mice. Small-interfering RNA (siRNA) and CRISPR/Cas9 were used to abrogate ARID1A in human pancreatic ductal epithelial cells.
Results We found that pancreas-specific Arid1a loss in mice was sufficient to induce inflammation, pancreatic intraepithelial neoplasia (PanIN) and mucinous cysts. Concurrent Kras activation accelerated the development of cysts that resembled intraductal papillary mucinous neoplasm. Lineage-specific Arid1a deletion confirmed compartment-specific tumour-suppressive effects. Duct-specific Arid1a loss promoted dilated ducts with occasional cyst and PDAC formation. Heterozygous acinar-specific Arid1a loss resulted in accelerated PanIN and PDAC formation with worse survival. RNA-seq showed that Arid1a loss induced gene networks associated with Myc activity and protein translation. ARID1A knockdown in human pancreatic ductal epithelial cells induced increased MYC expression and protein synthesis that was abrogated with MYC knockdown. ChIP-seq against H3K27ac demonstrated an increase in activated enhancers/promoters.
Conclusions Arid1a suppresses pancreatic neoplasia in a compartment-specific manner. In duct cells, this process appears to be associated with MYC-facilitated protein synthesis.
- pancreatic cancer
- pancreatic tumours
- cancer genetics
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
SCW and IN contributed equally.
Contributors SCW, IN and HZ conceived of and designed the experiments. SCW, IN, SX, SZ, LHN, J-CC performed experiments. LP and JS performed histological evaluations. XL and JL performed bioinformatics analyses. SCW and IN performed statistical calculations. SD provided key reagent and helped design the experiment. All authors contributed to data interpretation. SCW, IN and HZ wrote the manuscript.
Funding SCW was supported by the UT Southwestern Disease Oriented Clinical Scholarship, American College of Surgeon Faculty Research Fellowship, American Cancer Society Institutional Research Grant, and National Institutes of Health (NIH) 1K08CA222611 grant. IN was supported by the Alpha Omega Alpha Honor Medical Society, ChiRhoClin and the National Center for Advancing Translational Sciences of the NIH UL1TR001105. XS was supported by the Hamon Center for Regenerative Science and Medicine at UT Southwestern Medical Center. JL was supported by the Cancer Prevention Research Institute (CPRIT) (RP150596). HZ was supported by a Burroughs Wellcome Career Medical Award, CPRIT New Investigator Grant (R1209), CPRIT Early Translation Grant (DP150077), NIH/NIDDK R01DK111588, and a Stand Up To Cancer Innovative Research Grant (SU2C-AACR-IRG 10-16). Stand Up To Cancer is a program of the Entertainment Industry Foundation and its research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C.
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Competing interests SD is an employee and stockholder of Epizyme.
Patient consent Not required.
Ethics approval Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.