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Within a tumor, cancer stem cells (CSCs) represent a small yet highly aggressive, metastatic population that enhances the progression of the surrounding non-CSCs. Here we define lysophosphatidic acid (LPA) as a primary factor produced by pancreatic CSCs that converts non-CSCs to a stem-like fate. LPA promotes increased anchorage independence, drug resistance, self-renewal and stem gene expression including Oct4 and Nanog. Cancer stem cells were found to express high levels of the LPA producing enzyme cPLA2 explaining their production of LPA. Pancreatic cancer cells exposed to the drug Gemcitabine showed a dramatic upregulation of the LPA receptor 4 enabling the cells to become drug resistant and tolerant to a range of microenvironmental stresses. These finding indicate that LPA is a bioactive lipid produced by CSCs that converts surround pancreatic tumor cells to a highly aggressive state. Therapeutic intervention and/or microenvironmental stress will induce non-CSCs to express LPA Receptor 4, thereby making them stress tolerant and drug resistant. Evidence is provided that targeting the LPA receptor pathway may reverse this paracrine effect and thereby reverse cancer progression and drug resistance. Citation Format: Taha Rakhshandehroo, Jiali Tan, Brandon Grosshart, David Cheresh. Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-049.