Abstract 3348: Pax8-PPARδ fusion protein activates β-catenin/TCF pathways

Abstract

Abstract Pax8-PPARδ Fusion Protein (PPFP) occurs in ∼35% of follicular thyroid carcinomas. Expression of PPFP in the non-transformed rat thyroid cell line PCCL3 conferred on the cells the ability to invade through matrigel and to form colonies in anchorage independent conditions. PPFP also increased the percentage of cells that have activated β-catenin/TCF. We transfected control and PPFP expressing PCCL3 thyroid cell lines with two different β-catenin/TCF-GFP reporter systems. We then sorted a population of GFP positive cells and expanded them to obtain 100% transfected cell lines. These GFP positive cells gave rise to a new heterogenous population with a stable equilibrium between GFP positive, β-catenin/TCF active cells and GFP negative, β-catenin/TCF inactive cells. PPFP expressing cell lines contained more than twice the percentage of GFP positive cells compared to control cell lines. GFP positive PPFP expressing thyroid cells were enriched for cells exhibiting the transformed phenotypes previously observed in the unsorted, untransfected cell lines. Sorted β-catenin/TCF active single cells gave rise to heterogenous clonal populations containing both β-catenin/TCF active and negative cells. Clonal populations derived from β-catenin/TCF inactive cells remained purely negative. Clonal populations derived from GFP positive cells were twice as enriched for anchorage independent colony forming cells than GFP negative clones. More strikingly, GFP positive clones were 5-10 times more invasive than negative clones, which exhibited the same invasive potential as control cells. Treatment with PPARδ full or partial agonists further increased the β-catenin/TCF population in PPFP expressing cells. Again, the effects were confined to populations containing β-catenin/TCF active cells. Co-treatment with PPARδ antagonists reversed the effects of PPARδ agonists. These data suggest that β-catenin/TCF active cells have properties of cancer stem cells and that PPFP acts on this population to expand the stem cell like fraction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3348. doi:1538-7445.AM2012-3348