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Introduction: Cancer stem cells are highly resistant to chemotherapy and radiotherapy, and these cells are thought to be the basis of failure of palliative or adjuvant therapies for pancreatic cancers. Many characteristics of cancer stem cells, including their antiapoptotic nature and presence of multiple bypass pathways for nucleotide synthesis, make them attractive targets for replication-competent, oncolytic viruses. Methods: To determine if oncolytic viruses can specifically target and kill pancreatic cancer stem cells, a stem cell population from the MiaPaca-2 pancreatic adenocarcinoma cell line was isolated by FACS according to cell surface markers CD133 and CXCR4 and cultured in serum-free media. The stem cell spheroids were infected with NV1066, a third-generation herpesvirus, or NDV-F3aa-GFP, a Newcastle Disease virus mutant. Both viruses carried the marker gene green fluorescent protein (GFP), which allowed monitoring by fluorescent microscopy. Cell cycle analysis and cell migration assay were also performed.Results: Viral infection of cancer stem cells was rapid (GFP expression was seen by 24 hours). The viruses from both families each produced efficient infection and killing of cancer. At doses of multiplicity of infection (MOI, number of viruses per tumor cell) of 0.5 or 1, >95% of cells were dead by day 6. Infection with virus also produced decreased migratory capacity of the cancer stem cells and shifted the population to a higher fraction in S phase.Conclusion: Multiple types of oncolytic viruses effectively target the stem cell subpopulation of pancreatic cancer cells. Infection decreases metastatic potential and effects killing of such stem cells. These data support clinical studies of oncolytic viruses in the treatment of chemo- and radioresistant tumors.