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Supplementary Figure Legends from New Blocking Antibodies against Novel AGR2–C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice

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posted on 2023-04-03, 14:11 authored by Thiruvengadam Arumugam, Defeng Deng, Laura Bover, Huamin Wang, Craig D. Logsdon, Vijaya Ramachandran

Extracellular rAGR2-mediated functions, Candidate receptors binding and silencing, Silencing C4.4A reduced basal and rAGR2-mediated functions, Effects of AGR2 are mediated by C4.4A interacting with integrin beta 1, Monoclonal antibodies developed bind respectively to AGR2 and C4.4A proteins and blocked their functions, In Vivo treatment with AGR2/C4.4A antibodies reduced tumor volume are described as the experiment is conducted.

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ARTICLE ABSTRACT

Anterior gradient 2 (AGR2) promotes cancer growth, metastasis, and resistance to therapy via unknown mechanisms. We investigated the effects of extracellular AGR2 signaling through the orphan glycosylphosphatidylinositol-linked receptor C4.4A in pancreatic ductal adenocarcinoma (PDAC). Proliferation, migration, invasion, and apoptosis were measured using colorimetric, Boyden chamber, and FACS analyses. We developed blocking mAbs against AGR2 and C4.4A and tested their effects, along with siRNAs, on cancer cell functions and on orthotopic tumors in nude mice. Extracellular AGR2 stimulated proliferation, migration, invasion, and chemoresistance of PDAC cell lines. AGR2 interacted with C4.4A in cell lysates and mixtures of recombinant proteins. Knockdown of C4.4A reduced migration and resistance to gemcitabine. PDAC tissues, but not adjacent healthy pancreatic tissues, expressed high levels of AGR2 and C4.4A. AGR2 signaling through C4.4A required laminins 1 or 5 and integrin β1. Administration of antibodies against AGR2 and C4.4A reduced growth and metastasis and caused regression of aggressive xenograft tumors, leading to increased survival of mice. These data support a model in which AGR2 binds and signals via C4.4A in an autocrine loop and promotes the growth of pancreas tumors in mice. Blocking mAbs against AGR2 and C4.4A may have therapeutic potential against PDAC. Mol Cancer Ther; 14(4); 941–51. ©2015 AACR.

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