Here, we showed generation of a functional cleaved MUC16 that imparts tumorigenic, metastatic and drug resistant properties to PC cells partly by enrichment of ALDH+ CSCs, which in turn is dependent on nuclear JAK2 mediated up regulation of stemness specific genes LMO2 and NANOG. Therefore, it is conceivable that therapeutic strategies that can be targeted against MUC16-Cter will be critical in treating MUC16 expressing pancreatic cancer patients. This evidence concerns the gene LMO2 and pachyonychia congenita.