Unique mechanisms of growth regulation and tumor suppression upon Apc inactivation in the pancreas

Alessandra Strom, Claire Bonal, Ruth Ashery-Padan, Naoko Hashimoto, M. Luisa Campos, Andreas Trumpp, Tetsuo Noda, Yoshiaki Kido, Francisco X. Real, Fabrizio Thorel, Pedro L. Herrera*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

β-catenin signaling is heavily involved in organogenesis. Here, we investigated how pancreas differentiation, growth and homeostasis are affected following inactivation of an endogenous inhibitor of β-catenin, adenomatous polyposis coli (Apc). In adult mice, Apc-deficient pancreata were enlarged, solely as a result of hyperplasia of acinar cells, which accumulated β-catenin, with the sparing of islets. Expression of a target of β-catenin, the proto-oncogene c-myc (Myc), was increased in acinar cells lacking Apc, suggesting that c-myc expression is essential for hyperplasia. In support of this hypothesis, we found that conditional inactivation of c-myc in pancreata lacking Apc completely reversed the acinar hyperplasia. Apc loss in organs such as the liver, colon and kidney, as well as experimental misexpression of c-myc in pancreatic acinar cells, led to tumor formation with high penetrance. Surprisingly, pancreas tumors failed to develop following conditional pancreas Apc inactivation. In Apc-deficient acini of aged mice, our studies revealed a cessation of their exaggerated proliferation and a reduced expression of c-myc, in spite of the persistent accumulation of β-catenin. In conclusion, our work shows that β-catenin modulation of c-myc is an essential regulator of acinar growth control, and unveils an unprecedented example of Apc requirement in the pancreas that is both temporally restricted and cell-specific. This provides new insights into the mechanisms of tumor pathogenesis and tumor suppression in the pancreas.

Original languageEnglish
Pages (from-to)2719-2725
Number of pages7
JournalDevelopment (Cambridge)
Volume134
Issue number15
DOIs
StatePublished - Aug 2007

Keywords

  • Apc
  • Growth
  • ICAT
  • Mouse
  • Pancreas
  • c-myc
  • β-catenin

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