Activation of PPARδ initiates invasiveness and metastasis. A,PPARD mRNA expression upon 24 to 48 hours of treatment with MCM, etomoxir (Eto), and 5 μmol/L of the PPARδ agonist GW0742. Pooled data of PDAC-215, 253, and 354 cells (n = 4–7). B, Representative Western blot after 48 hours of treatment in PDAC-354 cells. C, PPARδ activity, measured as binding to the PPAR response element, following stimulation with MCM, etomoxir, and the PPARδ agonist GW0742 for 24 hours (n = 5). D, CUT&Tag analysis of PPARδ protein binding at the UCP1, PGC1A, and SNAI2 loci. WashU Epigenome browser tracks showing CUT&Tag signals at the mentioned loci with the indicated transcription start site (TSS). Blue signals represent PPARδ binding in control (Ctrl) conditions, and red signals represent PPARδ binding upon 24 hours of etomoxir treatment in PDAC-002 cells. E, Lipidomics analyses for PDAC-215 and PDAC-253 cells treated for 24 hours with MCM and etomoxir. OPLS-DA analysis showing the most represented lipids common for PDAC-215 and 253 for each experimental conditions vs. the control condition (n = 3). F, Venn diagram indicating the number of lipid species for each experimental group. The four common upregulated lipids for all four conditions are indicated in the square. G, Invasive capacity of cells treated for 48 hours with the PPARδ agonists L-165 and GW0742 (5 μmol/L). Cells were placed in modified Boyden invasion chambers containing 20% FBS in the lower compartment, and the number of invasive cells was assessed after 16 hours (n = 4–8). H, Experimental metastasis assay of PDAC-354-GFP-Luc cells pretreated with GW0742 for 48 hours. After intrasplenic injection, mice received three more daily doses of GW0742 (0.3 mg/kg i.v.). IVIS imaging (left) and quantification of the total CK-19 area in the livers 9 weeks after implantation (right). All data are represented as the mean ± SEM. *, P P
Parejo-Alonso et al. (Tue,) studied this question.