Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma
Open Access
- 5 October 2017
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 2 (19)
- https://doi.org/10.1172/jci.insight.92232
Abstract
Pancreatic ductal adenocarcinomas (PDAs) are desmoplastic and can undergo epithelial-to-mesenchymal transition to confer metastasis and chemoresistance. Studies have demonstrated that phenotypically and functionally distinct stromal cell populations exist in PDAs. Fibroblast activation protein–expressing (FAP-expressing) cells act to enhance PDA progression, while α–smooth muscle actin myofibroblasts can restrain PDA. Thus, identification of precise molecular targets that mediate the protumorigenic activity of FAP+ cells will guide development of therapy for PDA. Herein, we demonstrate that FAP overexpression in the tumor microenvironment correlates with poor overall and disease-free survival of PDA patients. Genetic deletion of FAP delayed onset of primary tumor and prolonged survival of mice in the KPC mouse model of PDA. While genetic deletion of FAP did not affect primary tumor weight in advanced disease, FAP deficiency increased tumor necrosis and impeded metastasis to multiple organs. Lineage-tracing studies unexpectedly showed that FAP is not only expressed by stromal cells, but can also be detected in a subset of CD90+ mesenchymal PDA cells, representing up to 20% of total intratumoral FAP+ cells. These data suggest that FAP may regulate PDA progression and metastasis in cell-autonomous and/or non-cell-autonomous fashions. Together, these data support pursuing FAP as a therapeutic target in PDA.Funding Information
- National Institutes of Health (R21 CA169741, R01 CA141144, R01 CA 172921)
- Cancer Research Institute (Student Training, Research in Tumor Immunology Fellowship)
- Academia Sinica and Ministry of Science and Technology (MOST 106-0210-01-15-02)
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