Coadaptation fostered by the SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma

Qing Li, Xiao-Xin Zhang, Li-Peng Hu, Bo Ni, Dong-Xue Li, Xu Wang, Shu-Heng Jiang, Hui Li, Min-Wei Yang, Yong-Sheng Jiang, Chun-Jie Xu, Xue-Li Zhang, Yan-Li Zhang, Pei-Qi Huang, Qin Yang, Yang Zhou, Jian-ren Gu, Gary Gui-Shan Xiao, Yong-wei Sun (), Jun Li () and Zhi-Gang Zhang ()
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Qing Li: Shanghai Jiao Tong University
Xiao-Xin Zhang: Shanghai Jiao Tong University
Li-Peng Hu: Shanghai Jiao Tong University
Bo Ni: Shanghai Jiao Tong University
Dong-Xue Li: Shanghai Jiao Tong University
Xu Wang: Shanghai Jiao Tong University
Shu-Heng Jiang: Shanghai Jiao Tong University
Hui Li: Shanghai Jiao Tong University
Min-Wei Yang: Shanghai Jiao Tong University
Yong-Sheng Jiang: Shanghai Jiao Tong University
Chun-Jie Xu: Shanghai Jiao Tong University
Xue-Li Zhang: Shanghai Jiao Tong University
Yan-Li Zhang: Shanghai Jiao Tong University
Pei-Qi Huang: Shanghai Jiao Tong University
Qin Yang: Shanghai Jiao Tong University
Yang Zhou: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Jian-ren Gu: Shanghai Jiao Tong University
Gary Gui-Shan Xiao: Dalian University of Technology
Yong-wei Sun: Shanghai Jiao Tong University
Jun Li: Shanghai Jiao Tong University
Zhi-Gang Zhang: Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.

Date: 2023
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DOI: 10.1038/s41467-023-36521-0

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