Abstract B058: The lincRNA Neat1 controls SWI/SNF occupancy to retain ductal cell identity in the pancreas

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the US and among the most fatal. Cancer originating from the ductal compartment often leads to the emergence of the highly aggressive basal subtype of PDAC. Defining the cellular and molecular origins of basal subtype PDAC would greatly improve our ability to devise strategies to treat patients with this aggressive form of PDAC. Towards this end, we have discovered that loss of the long intergenic non-coding RNA (lincRNA) Neat1 promotes ductal cell plasticity, dramatically inducing the formation of duct-derived preneoplastic lesions known as intraductal papillary mucinous neoplasms (IPMNs), and increasing the likelihood of basal subtype PDAC. Neat1 deficiency has a profound impact on chromatin organization and on the distribution of the SWI/SNF chromatin remodeling complex at the chromatin, suggesting that Neat1 maintains ductal cell identity via impacting SWI/SNF function. Probing for Brg1, a core component of the SWI/SNF complex, we demonstrated that Neat1 loss leads to decreased SWI/SNF binding at enhancer regions. This idea is further supported by the phenotypic similarities between mice deficient for Neat1 and Arid1a. We thus hypothesize that Neat1 and SWI/SNF are critical for the maintenance of ductal cell identity in the pancreas via controlling SWI/SNF-dependent enhancer activity and that loss of Neat1 increases ductal cell transformation and thus facilitates IPMN formation and progression to basal subtype PDAC. These studies will reveal both the biological role and mechanistic underpinnings of the lincRNA Neat1 in relationship with the SWI/SNF chromatin remodeling complexes. Our data suggest that Neat1 or SWI/SNF loss-of-function predisposes pancreatic ductal cells towards the most aggressive subtype of PDAC, laying critical groundwork for development of new diagnostic tools and therapeutic targets. Citation Format: Emily Berry, Zamira Guerra Soares, Jennifer Twardowski, Wenjia Wang, Aram Hezel, Stephano S. Mello. The lincRNA Neat1 controls SWI/SNF occupancy to retain ductal cell identity in the pancreas [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B058.