TY - JOUR
T1 - p120 catenin suppresses basal epithelial cell extrusion in invasive pancreatic neoplasia
AU - Hendley, Audrey M.
AU - Wang, Yue J.
AU - Polireddy, Kishore
AU - Alsina, Janivette
AU - Ahmed, Ishrat
AU - Lafaro, Kelly J.
AU - Zhang, Hao
AU - Roy, Nilotpal
AU - Savidge, Samuel G.
AU - Cao, Yanna
AU - Hebrok, Matthias
AU - Maitra, Anirban
AU - Reynolds, Albert B.
AU - Goggins, Michael
AU - Younes, Mamoun
AU - Iacobuzio-Donahue, Christine A.
AU - Leach, Steven D.
AU - Bailey, Jennifer M.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84975082536&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-2268
DO - 10.1158/0008-5472.CAN-15-2268
M3 - Article
C2 - 27032419
AN - SCOPUS:84975082536
SN - 0008-5472
VL - 76
SP - 3351
EP - 3363
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -