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Abstract PR-005: Chromatin dynamics in vivo define coordinate functions of inflammation and mutant Kras in pancreatic tumorigenesis

Authors :
Alexa Osterhoudt
Jason R. Pitarresi
Steven D. Leach
Rohit Chandwani
Adrien Grimont
David J. Falvo
Ben Z. Stanger
Anil K. Rustgi
Source :
Cancer Research. 81:PR-005
Publication Year :
2021
Publisher :
American Association for Cancer Research (AACR), 2021.

Abstract

Pancreatic cancer initiation features abundant rewiring of the normal acinar cell,. but little is known about the chromatin specification of pancreatic cell types and the epigenetic dysregulation of normal acinar cells in tumor initiation. To address these questions, we employed a lineage-traced autochthonous mouse model to examine systematically perturbed acinar cells. We coupled the spatiotemporal control of inflammation (via caerulein injections) with inducible oncogene activation (mutant Kras) in the adult mouse along with bulk RNA-seq and ATAC-seq to sorted acinar and acinar-derived cells. In addition, we generated Ptf1a-TdTomato mice to reliably sort pancreatic progenitors at e10.5 and e15.5. We observe that Kras activation alone does not disturb acinar cell chromatin nor the histologic appearance of the pancreas. By contrast, caerulein alters chromatin significantly in metaplasia and even in regeneration, with putative enhancers derepressed despite normal histology. In the context of Kras activation and caerulein administration, we find a broad and stable reorganization of chromatin, reflecting cooperativity between oncogenic stress and an inflammatory insult. We also find that in PanIN, the chromatin state bears few, if any, ductal, progenitor, or islet features and instead reflects a largely novel cell fate. To understand the dependencies of these findings on an inflammatory insult and mutant Kras, we leveraged temporal resolution of pancreatitis and the iKras system to define the reversibility of this epigenetic rewiring. Notably, neither resolution of inflammation nor withdrawal of mutant Kras expression are sufficient to revert an acinar cell to its initial chromatin state. Analysis of the acinar-derived cells undergoing the transition to PanIN reveals the induction of specific proliferative and progenitor master transcription factors and activation of associated transcriptional programs. In these data we also observe a specific unveiling of the AP-1 isoform Fra-1 (Fosl1) transcript, protein, and binding sites in chromatin. To address if Fra-1-associated alterations to chromatin are bona fide requirements for tumorigenesis, we coupled conditional Fra-1 knockout alleles with the iKras system, finding nearly complete ablation of PanIN in the absence of Fra-1. Together, our findings suggest that (1) loss of acinar cell identity is resistant to oncogenic stress and is susceptible to inflammation; (2) the acquired acinar cell fate reflects neither ‘pure’ metaplasia nor transdifferentiation nor dedifferentiation events, and (3) acinar cell regeneration is incomplete. In contrast to recent studies, we demonstrate that pancreatic tumorigenesis does not re-establish a progenitor cell fate, but hijacks the AP-1 transcription factors for tumor-specific genomic locations, with Fra-1 emerging as a dependency in tumorigenesis. Our data thus highlight the complexity of cell fate decisions in the preneoplastic pancreas and reveal key regulators of acinar cell identity. Citation Format: David Falvo, Jason Pitarresi, Alexa Osterhoudt, Adrien Grimont, Ben Stanger, Steven D. Leach, Anil K. Rustgi, Rohit Chandwani. Chromatin dynamics in vivo define coordinate functions of inflammation and mutant Kras in pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-005.

Details

ISSN :
15387445 and 00085472
Volume :
81
Database :
OpenAIRE
Journal :
Cancer Research
Accession number :
edsair.doi...........736212c52b49854995cf09f63a1621fd
Full Text :
https://doi.org/10.1158/1538-7445.panca21-pr-005