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Zebrafish is establishing itself as a powerful animal model for understanding human disease, including cancer. Xenotransplantation of human cancer cells into zebrafish is becoming an attractive research tools for studying cancer behaviour, both for established lines and primary tumours, however, its utility as a model for cancer stem cells (CSCs) is still in its infancy. In addition, only when the differences between primary tumours and established cancer cell lines are minimized will we be truly one step closer to developing biologically relevant personalized medicine platforms for cancer. To address these two limitations, we set out to achieve a deeper behavioral understanding of pancreatic CSCs inside the zebrafish embryo. The main methodology of this study was focused on the xenotransplantation of human primary pancreatic ductal adenocarcinoma (PDAC) cells (185 scd line) into zebrafish embryos using two different conditions: adherent cells (non-CSCs) vs sphere-derived cells (CSCs). Marked with a lipophilic dye, cells were injected into zebrafish embryos and incubated at 36ºC during 48h/72h to assess the proliferation of the injected cells. Self-developed Matlab software was used to analyze the intensity and area of the injected cells in order to give a ‘proliferation ratio’. Results obtained indicated that the sphere-derived cells proliferated and migrated at a higher rate than adherent cells. This is likely due to the different CSC content present between the two conditions tested: adherent pancreatic 185 cells contain 1% CSCs versus the 15% enrichment of CSCs in sphere-derived 185 cells. Apart from the differential CSC content, we also hypothesize that the 3D environment afforded by the yolk sac of the zebrafish embryo additionally favors the expansion of CSCs. Importantly, similar results were obtained with CSCs isolated via FACsorting, using autofluorescence as a marker for CSCs. This work not only contributes to the behavioral understanding of pancreatic CSCs using the zebrafish model organism but more importantly concludes that 1) PDAC CSC proliferation and migration can be studied in zebrafish, 2) the zebrafish model represents a potentially powerful surrogate model for the study of PDAC CSC biology in vivo, and 3) this model can potentially be adapted for to test chemotherapeutics that specifically target PADC CSCs, the cell type considered to be the most chemoresistant and tumorigenic in pancreatic cancer. Citation Format: Laura E. Sanchez, Pablo Cabezas Sainz, Bruno Sainz, Laura Muinelo, Rafael Lopez. Zebrafish as a model organism to study human pancreatic CSC's [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 804. doi:10.1158/1538-7445.AM2017-804