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Interplay of ARID1A and EGFR signaling in controlling acinar cell reprogramming in the pancreas

dc.contributor.advisorHessmann, Elisabeth Prof. Dr.
dc.contributor.authorZhang, Zhe
dc.titleInterplay of ARID1A and EGFR signaling in controlling acinar cell reprogramming in the pancreasde
dc.contributor.refereeWollnik, Bernd Prof. Dr.
dc.description.abstractengBased on a high degree of cellular plasticity and triggered by external (e.g. inflammation) or internal (e.g. oncogenic pressure) signals, pancreatic acinar cells can undergo reprogramming processes resulting in acinar-to-ductal metaplasia (ADM). Functionally, ADM is involved in pancreatic regeneration processes, but also represents the initiating event of pancreatic carcinogenesis. Acinar reprogramming is under coordinated regulation of genetic, epigenetic and environmental factors, among which, SWItch/Sucrose Non-Fermentable (SWI/SNF) -mediated chromatin remodeling plays a pivotal role. The SWI/SNF complex, and particularly its DNA-binding subunit AT-rich interaction domain-containing protein 1A (ARID1A), is crucial for determining cell fate and maintaining terminal cell differentiation. Loss-of-function mutations of ARID1A, as recurrently detected in PDAC patients, lead to aberrant chromatin regulation and altered gene transcription, and have been shown to disrupt acinar cell homeostasis and accelerate oncogenic Kras-driven pancreatic carcinogenesis. However, the mechanistic background of ARID1A-dependent maintenance of acinar cell integrity and the interaction of the SWI/SNF member with upstream signaling cues have not been elucidated yet. Herein, we aimed at i) exploring the consequences of ARID1A loss on chromatin regulation during acinar-to-ductal metaplasia, and ii) characterizing the interplay of ARID1A with epidermal growth factor receptor (EGFR) signaling, a known inducer of ADM, in determining acinar cell fate. In order to dissect how EGFR signaling and ARID1A-mediated chromatin regulation interact in acinar reprogramming we combined in vivo and in vitro models with high-throughput sequencing methods. We confirmed that Arid1a deficiency drives ADM in the pancreas which is accompanied by upregulation of EGFR expression. Arid1a-deficiency and EGFR signaling cooperate in promoting the ADM phenotype. Furthermore, we showed that the cooperation between EGFR signaling activation and Arid1a deficiency in acinar cell reprogramming was executed through creating a chromatin state permissive ductal gene transcription program. Moreover, EGFR interferes with ARID1A-dependent transcriptional regulation by reducing genome-wide occupancy of ARID1A, thus phenocopying Arid1a deficiency in driving acinar to ductal metaplasia (ADM). Mechanistically, we identified the Nuclear Factor of Activated T cells cytoplasmic 1 (NFATc1) transcription factor as the integrating signaling cue that elicits ARID1A genomic dissociation from chromatin in response to EGFR signaling activation, thus driving ADM. In conclusion, we demonstrate a novel EGFR-NFATC1-ARID1A regulatory axis in promoting pancreatic acinar reprogramming and provide mechanistic insights into the upstream epigenetic regulation of ARID1A
dc.contributor.coRefereePapantonis, Argyris Prof. Dr.
dc.contributor.thirdRefereeDobbelstein, Matthias Prof. Dr.
dc.contributor.thirdRefereeGünesdogan, Ufuk Dr.
dc.contributor.thirdRefereePosnien, Nico Dr.
dc.subject.engpancreatic cancerde
dc.subject.engacinar-to-ductal metaplasiade
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullMedizin (PPN619874732)de

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