Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines.
Pancreatic cancer has an extremely high mortality rate due to its aggressive metastatic nature. Resolving the underlying mechanisms will be crucial for treatment. Here, we found that overexpression of IL-17B receptor (IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients. Consistently, results from ex vivo experiments further validated that IL-17RB and its ligand, IL-17B, plays an essential role in pancreatic cancer metastasis and malignancy. Signals from IL-17B-IL-17RB activated CCL20/CXCL1/IL-8/TFF1 chemokine expressions via the ERK1/2 pathway to promote cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival at distant organs. Treatment with a newly derived monoclonal antibody against IL-17RB blocked tumor metastasis and promoted survival in a mouse xenograft model. These findings not only illustrate a key mechanism underlying the highly aggressive characteristics of pancreatic cancer but also provide a practical approach to tackle this disease.
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Heng-Hsiung
HH
Wu
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Wendy W
WW
Hwang-Verslues
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Wen-Hsin
WH
Lee
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Chun-Kai
CK
Huang
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Pei-Chi
PC
Wei
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Chia-Lin
CL
Chen
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Jin-Yuh
JY
Shew
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697.
Eva Y-H P
EY
Lee
Department of Pathology and Department of Surgery, National Taiwan University Hospital, Taipei 10617, Taiwan.
Yung-Ming
YM
Jeng
Department of Pathology and Department of Surgery, National Taiwan University Hospital, Taipei 10617, Taiwan.
Yu-Wen
YW
Tien
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Che
C
Ma
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan Graduate Institute of Clinical Medicine, China Medical University, Taichung 40402, Taiwan whlee@uci.edu.
Wen-Hwa
WH
Lee
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018925:Chemokines / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018925:Chemokines; D020381:Interleukin-17; D053722:Receptors, Interleukin-17