Journal
CANCER RESEARCH
Volume 77, Issue 1, Pages 41-52Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-1383
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Funding
- Viragh Foundation
- Skip Viragh Pancreatic Cancer Center at Johns Hopkins
- NCI SPORE in Gastrointestinal Cancers [P50 CA062924]
- Lustgarten Foundation grant
- [NIHR01 CA169702]
- [NIHK23 CA148964 01]
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Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the prometastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth, and metastasis. Taken together, our results illuminate tumor-stromal interactions, which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC. (C) 2016 AACR.
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