Lineage Labeling Elucidates The Natural History Of Metastatic Colonization

Compared to primary tumor formation and invasion, relatively little is known about later stages of the metastatic cascade, including the seeding and colonization of distal tissues. To visualize these late steps in metastasis, we have generated an autochthonous mouse model of pancreatic ductal adenocarcinoma in which all pancreatic epithelial cells are genetically labeled with yellow fluorescent protein (the KPCY model). This system allows for the detection of single seeded tumor cells in distant organs, as well as micrometastasis and larger lesions. We have assessed the size distribution of metastatic lesions in two frequently colonized organs, the liver and lung, and found that single cells and clusters consisting of less than ten cells represent the majority of lesions in both tissues; however these small lesions only progress to gross metastasis in the liver, not the lung. We have previously used the KPCY model to study the dynamic process of epithelial-mesenchymal transition (EMT) and its involvement in invasion and dissemination from the primary tumor. We have extended these studies to assess the role of EMT and the reverse phenomenon, mesenchymal-epithelial transition (MET), in seeding and colonization at metastatic sites. Our results suggest that while EMT is favored for entry into the circulation, there may be selection for epithelial tumor cells or MET at the metastatic site. Additionally this model allows us to investigate the parallel evolution of metastatic lesions, from single cells to macrometastasis, and the associated metastatic microenvironment. Citation Format: Nicole M. Aiello, David L. Bajor, Robert H. Vonderheide, Ben Z. Stanger. Lineage labeling elucidates the natural history of metastatic colonization. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR14.