Abstract 5176: Chemotherapy alters the natural history of metastatic progression
2015
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of less than 6%. Metastatic disease accounts for a majority of PDAC-related deaths, even for patients with no evidence of metastasis at the time of resection. In this study we sought to understand the natural history of metastatic colonization and the cellular mechanisms governing the metastatic cascade. Using an autochthonous PDAC mouse model combined with a lineage-labeling approach, we have tracked and characterized the various stages of metastatic progression, from single cells to macroscopic lesions. PDAC tumors primarily metastasize to the liver, where small lesions of 10 cells or less reside closest to portal veins and exhibit a high frequency of epithelial-mesenchymal transition (EMT). Larger metastatic lesions exhibit reduced EMT and are hypovascular, resembling primary PDAC tumors. Metastases gradually accumulate desmoplasia as they grow, which consists of myofibroblasts, leukocytes and extracellular matrix components including collagen, hyaluronic acid, fibronectin and SPARC. Treatment with gemcitabine and nab-paclitaxel reduces overall metastatic burden and shifts the size distribution of metastases toward small lesions of 10 cells or less. Single seeded cells in particular seem to be protected from chemotherapy-induced killing, while larger lesions that have accumulated a desmoplastic stroma are more susceptible. Our results demonstrate that chemotherapy has direct measurable effects on metastatic burden, which may explain the improved outcomes for PDAC patients who receive adjuvant chemotherapy. Citation Format: Nicole M. Aiello, David L. Bajor, Minh N. Pham, Robert H. Vonderheide, Ben Z. Stanger. Chemotherapy alters the natural history of metastatic progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5176. doi:10.1158/1538-7445.AM2015-5176
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