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Targeting ErbB3-mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma
J S Liles1, J P Arnoletti, A V Kossenkov
1Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Background:
We sought to investigate the role of ErbB3-mediated signalling on the interaction between pancreatic cancer-associated fibroblasts (CAF) and carcinoma cells in an effort to disrupt tumourigenic pancreatic ductal adenocarcinoma (PDAC) stromal-epithelial cross-communication.
Methods:
Primary CAF cultures were established from human PDAC surgical specimens. AsPC-1 pancreatic cancer cell murine subcutaneous xenografts were developed in the presence and absence of CAF and were subsequently treated with epidermal growth factor receptor (EGFR) inhibitors (erlotinib) and ErbB3 inhibitors (MM-121, monoclonal ErbB3 antibody).
Results:
Cancer-associated fibroblasts were found to secrete neuregulin-1 (NRG-1), which promoted proliferation via phosphorylation of ErbB3 and AKT in AsPC-1 PDAC cells. This signalling cascade was effectively inhibited both in vitro and in vivo by specific ErbB3 blockade with MM-121, with greater degree of tumourigenesis inhibition when combined with erlotinib. The CAF-AsPC-1 pancreatic cancer xenografts reached significantly greater tumour volume than those xenografts lacking CAF and were resistant to the anti-tumour effects of EGFR inhibition with erlotinib.
Conclusion:
Cancer-associated fibroblasts-derived NRG-1 promote PDAC tumourigenesis via ErbB3-AKT signalling and overcomes single-agent EGFR inhibition. Disruption of this stromally mediated tumourigenic mechanism is best obtained through combined EGFR-ErbB3 inhibition with both erlotinib and MM-121. We have identified the NRG-1/ErbB3 axis as an attractive molecular target for the interruption of tumourigenic stromal-epithelial interactions within the PDAC microenvironment.
Insights
Pancreatic cancer-associated fibroblasts promote tumour growth via NRG-1/ErbB3 signalling, overcoming EGFR inhibition. Combined ErbB3 and EGFR blockade effectively inhibits pancreatic ductal adenocarcinoma tumourigenesis.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Signalling
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is driven by complex stromal-epithelial interactions.
- Cancer-associated fibroblasts (CAFs) play a critical role in PDAC tumourigenesis.
- Understanding CAF-epithelial cell communication is key to disrupting PDAC progression.
Purpose of the Study:
- To investigate the role of ErbB3-mediated signalling in CAF-carcinoma cell interactions.
- To identify therapeutic strategies to disrupt tumourigenic PDAC stromal-epithelial cross-communication.
Main Methods:
- Primary CAF cultures were derived from human PDAC surgical specimens.
- Murine subcutaneous xenografts of AsPC-1 PDAC cells were established with and without CAFs.
- Xenografts were treated with EGFR inhibitors (erlotinib) and ErbB3 inhibitors (MM-121).
Main Results:
- CAFs secrete neuregulin-1 (NRG-1), promoting PDAC cell proliferation via ErbB3-AKT signalling.
- ErbB3 blockade with MM-121 inhibited this signalling in vitro and in vivo.
- Combined erlotinib and MM-121 demonstrated superior tumourigenesis inhibition compared to single agents.
- CAF-PDAC xenografts showed resistance to single-agent EGFR inhibition.
Conclusions:
- CAF-derived NRG-1 drives PDAC tumourigenesis through the ErbB3-AKT pathway, circumventing single-agent EGFR inhibition.
- Combined inhibition of EGFR and ErbB3 (erlotinib and MM-121) is a promising strategy to disrupt CAF-mediated tumourigenesis.
- The NRG-1/ErbB3 axis represents a viable molecular target for interrupting PDAC stromal-epithelial interactions.
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