American Association for Cancer Research
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Figures S1-S8 from p120 Catenin Suppresses Basal Epithelial Cell Extrusion in Invasive Pancreatic Neoplasia

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journal contribution
posted on 2023-03-30, 23:45 authored by Audrey M. Hendley, Yue J. Wang, Kishore Polireddy, Janivette Alsina, Ishrat Ahmed, Kelly J. Lafaro, Hao Zhang, Nilotpal Roy, Samuel G. Savidge, Yanna Cao, Matthias Hebrok, Anirban Maitra, Albert B. Reynolds, Michael Goggins, Mamoun Younes, Christine A. Iacobuzio-Donahue, Steven D. Leach, Jennifer M. Bailey

This file contains Figures S1-S8. Figure S1 shows examples of representative images used to score p120 catenin expression in human TMAs and pancreatic histology of mice with loss of p120 catenin. Figure S2 depicts recruitment of inflammation and a unique stromal composition in KCiMist1; p120f/wt and KCiMist1; p120f/f pancreata. Figure S3 shows that prominent basal epithelial cell extrusion in pancreata of KCiMist1; p120f/f mice is not associated with incomplete EMT. Figure S4 shows that pancreatic loss of p120 catenin in a mouse model of acute pancreatitis delays regeneration and results in significant recruitment of inflammation, observations which are mediated at least in part through activation of NF-kB. Figure S5 illustrates that a subset of epithelial cells extruding apically in KCiMist1; p120wt/wt, KCiMist1; p120f/wt, and KCiMist1; p120f/f pancreata express cleaved Caspase-3, while epithelial cells extruding basally do not express cleaved Caspase-3. Figure S6 depicts an analysis of chromosome content using Feulgen stain, which showed abnormal DNA content and aneuploidy in a subset of basally extruded epithelial cells in KCiMist1; p120f/f pancreata. Figure S7 shows mislocalized p120 catenin expression in greater than 95% isolated epithelial cells in human PDA. Figure S8 illustrates IPA results of microarray performed on GFP+ pancreatic cells of KCiMist1G; p120wt/wt and KCiMist1G; p120f/f mice as well as IHC of select targets identified from IPA results.



AACR/Pancreatic Cancer Action Network Pathway to Leadership Award and by Texas Medical Center Digestive Diseases Center



Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351–63. ©2016 AACR.