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The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma

Nature Cell Biology volume 16, pages 255267 (2014) | Download Citation


Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN–PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN–PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.

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We thank C. Wright for sharing Ptf1a–Cre and Ptf1a–CreER mice, D. Tuveson for KrasG12D mice, and P. Chambon and D. Reisman for Brg1flox mice, respectively. We thank C. Austin and D. Ngow for tissue processing and excellent technical assistance and all M.H. laboratory members for helpful discussion. Work in M.H.’s laboratory was supported by a grant from the NIH (CA112537). G.v.F. was supported by a post-doctoral Research Fellowship from the Deutsche Forschungsgemeinschaft (DFG, FI 1719/1-1) and a Klein Family Foundation Fellowship. A.F. was supported by a post-doctoral Research Fellowship from the Japan Society for the Promotion of Science, a Fellowship from the US National Pancreas Foundation, and a Fellowship from the Kato Memorial Biosciences Foundation. M.E.L. was supported by CIRM training grant TG2 01153. W.F.M., A.B. and K.J.H. were supported by a grant from the NIH (CA149548). Image acquisition was supported by the imaging core of the UCSF Diabetes and Endocrinology Research Center (DERC) NIH grant P30DK63720.

Author information

Author notes

    • Guido von Figura
    • , Akihisa Fukuda
    • , Nilotpal Roy
    •  & Muluye E. Liku

    These authors contributed equally to this work.


  1. Diabetes Center, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW 1116, Box 0540 San Francisco, California 94143, USA

    • Guido von Figura
    • , Akihisa Fukuda
    • , Nilotpal Roy
    • , Muluye E. Liku
    • , John P. Morris IV
    • , Holger A. Russ
    •  & Matthias Hebrok
  2. II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany

    • Guido von Figura
  3. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

    • Akihisa Fukuda
  4. Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA

    • Grace E. Kim
  5. Department of Surgery

    • Matthew A. Firpo
    •  & Sean J. Mulvihill
  6. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84115, USA

    • Matthew A. Firpo
    •  & Sean J. Mulvihill
  7. Department of Pathology, University of California, Los Angeles, California 90095, USA

    • David W. Dawson
  8. Department of Medicine, Imperial College London, W12 ONN London, UK

    • Jorge Ferrer
  9. Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697, USA

    • William F. Mueller
    • , Anke Busch
    •  & Klemens J. Hertel


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G.V.F., A.F., N.R. and M.E.L. contributed to equal parts. G.V.F., A.F., N.R. and M.E.L. carried out all experiments and were involved together with M.H. in design and analysis of the experiments. G.V.F., A.F., N.R., M.E.L. and M.H. drafted the manuscript. J.P.M.I.V. generated cell lines, contributed to the survival analysis, was involved in experimental analysis, and critically reviewed the manuscript. G.E.K. performed the histopathological analysis including IPMN and tumour identification and tumour grading. H.R. performed quantification of tumour proliferation. J.F. generated the HNF1b–CreERT2 mice. D.W.D. analysed Brg1 expression on human samples. M.A.F., S.J.M. and J.F. provided intellectual contribution to this study. M.F.W., A.B. and K.J.H. carried out deep sequencing analyses. M.H. conceived the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Matthias Hebrok.

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