In:
Genes & Development, Cold Spring Harbor Laboratory, Vol. 30, No. 17 ( 2016-09-01), p. 1943-1955
Abstract:
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras -driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened ( Smo ) in stromal fibroblasts in a Kras G12D mouse model increased ADM. Smo -deleted fibroblasts had higher expression of transforming growth factor-α ( Tgfa ) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo . Additionally, Smo -deleted fibroblasts stimulated the growth of Kras G12D / Tp53 R172H pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras G12D -driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
Type of Medium:
Online Resource
ISSN:
0890-9369
,
1549-5477
DOI:
10.1101/gad.283499.116
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2016
detail.hit.zdb_id:
1467414-2
SSG:
12