Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice with Activated KRAS

Wanglong Qiu, Sophia M. Tang, Sohyae Lee, Andrew T. Turk, Anthony N. Sireci, Anne Qiu, Christian Rose, Chuangao Xie, Jan Kitajewski, Hui Ju Wen, Howard C. Crawford, Peter A. Sims, Ralph H. Hruban, Helen E. Remotti, Gloria H. Su

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Background & Aims Activin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis. Methods We disrupted Acvr1b specifically in pancreata of mice (Acvr1bflox/flox;Pdx1-Cre mice) and crossed them with LSL-KRASG12D mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Acvr1bflox/flox;LSL-KRASG12D;Pdx1-Cre mice were monitored; pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. We also analyzed p16flox/flox;LSL-KrasG12D;Pdx1-Cre mice and Cre-negative littermates (controls). Genomic DNA, total RNA, and protein were isolated from mouse tissues and primary pancreatic tumor cell lines and analyzed by reverse-transcription polymerase chain reaction, sequencing, and immunoblot analyses. Human intraductal papillary mucinous neoplasm (IPMN) specimens were analyzed by immunohistochemistry. Results Loss of ACVR1B from pancreata of mice increased the proliferation of pancreatic epithelial cells, led to formation of acinar to ductal metaplasia, and induced focal inflammatory changes compared with control mice. Disruption of Acvr1b in LSL-KRASG12D;Pdx1-Cre mice accelerated the growth of pancreatic IPMNs compared with LSL-KRASG12D;Pdx1-Cre mice, but did not alter growth of pancreatic intraepithelial neoplasias. We associated perinuclear localization of the activated NOTCH4 intracellular domain to the apical cytoplasm of neoplastic cells with the expansion of IPMN lesions in Acvr1bflox/flox;LSL-KRASG12D;Pdx1-Cre mice. Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1bflox/flox;LSL-KrasG12D;Pdx1-Cre mice. We also observed progressive loss of p16 in human IPMNs of increasing grades. Conclusions Loss of ACVR1B accelerates growth of mutant KRAS-induced pancreatic IPMNs in mice; this process appears to involve NOTCH4 and loss of p16. ACVR1B suppresses early stages of pancreatic tumorigenesis; the activin signaling pathway therefore might be a therapeutic target for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)218-228.e12
JournalGastroenterology
Volume150
Issue number1
DOIs
StatePublished - Jan 1 2016

    Fingerprint

Keywords

  • Pancreas
  • PDA
  • TGF-β Superfamily
  • Tumor Suppressor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Qiu, W., Tang, S. M., Lee, S., Turk, A. T., Sireci, A. N., Qiu, A., Rose, C., Xie, C., Kitajewski, J., Wen, H. J., Crawford, H. C., Sims, P. A., Hruban, R. H., Remotti, H. E., & Su, G. H. (2016). Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice with Activated KRAS. Gastroenterology, 150(1), 218-228.e12. https://doi.org/10.1053/j.gastro.2015.09.013