Journal: Molecular Cancer
Article Title: c-Rel drives pancreatic cancer metastasis through fibronectin-integrin signaling-induced isolation stress resistance and EMT
doi: 10.1186/s12943-025-02486-5
Figure Lengend Snippet: A Colony-forming frequency was assessed by the ability of cells to form an organoid in Matrigel (one-way ANOVA, p=0.0015). Tukey's multiple comparisons test results are shown in the figure. B Representative microscopy images of spheroids formed under nonadherent conditions. The average spheroid diameter was quantified and analyzed (genotype factor p=0.0227). C Representative spheroid images and their diameter quantification. The spheroid medium was supplemented with either human plasma fibronectin (pFN1) or cellular fibronectin with EDB domain + type II domains 8−14 (EDB cFN1.3) (treatment factor p= n.s.) D Surface expression of selected proteins on spheroids as assessed by flow cytometry analysis (one-way ANOVA test for CD61 p=0.0244, CD133, EpCAM, CD44, CXCR4, Sca1 p= n.s.). Tukey's multiple comparisons test results are shown in the figure. E Representative macroscopic and microscopic images of the transplanted mouse lungs. The number of cell lines used per genotype are CKP=5, GCKP=5 and FNGCKP=4. Each cell line was injected two times to two individual mice. Nested one-way ANOVA was used for both analyses. Tukey's multiple comparisons test results are shown in the figure. Unless otherwise indicated, for all analyses, two-way ANOVA was used. ANOVA p values are given in the figure or their legends. Šídák's multiple comparison tests between genotypes are shown in the figures. F Schematic depicting the function of c-Rel in PDAC pathophysiology. c-Rel is an oncogenic factor involved in PDAC survival and metastasis. Increased c-Rel expression remodels the ECM by converting the collagen-rich stroma to a fibronectin-rich stroma. Cancer cells undergo epithelial-to-mesenchymal transition, increasing EMP by reducing the surface expression of E-cadherin and contractility via Src and Stat3 phosphorylation. Once isolation stress is induced under nonadherent conditions, c-Rel induces a niche enriched with fibronectin, coupled with increased Itgb3, Itga5 and Itgav expression. These changes are also supported by EMP, where c-Rel directly induces EMT-TFs such as Snai1, Snai2, Zeb2, and Tgfb . Increased tolerance to isolation stress ultimately drives metastasis. Created in BioRender. Kabacaoglu, D. (2025)
Article Snippet: The serum samples were diluted 1:8000 and analyzed with a Mouse Fibronectin ELISA Kit (Novus, NBP2-60517).
Techniques: Microscopy, Clinical Proteomics, Expressing, Flow Cytometry, Injection, Comparison, Phospho-proteomics, Isolation