| Autor: |
Qing Li, Xiao-Xin Zhang, Li-Peng Hu, Bo Ni, Xu Wang, ShuHeng Jiang, Min-Wei Yang, Yong-shen Jiang, Chun-Jie Xu, Xueli Zhang, Yanli Zhang, Pei-Qi Huang, Qin Yang, Yang Zhou, Jian-ren Gu, Gary Gui-Shan Xiao, Yong-Wei Sun, Jun Li, Zhi-Gang Zhang |
| Rok vydání: |
2021 |
| DOI: |
10.21203/rs.3.rs-76006/v1 |
| Popis: |
To explore the mechanism of co-evolution and potential driver of which in pancreatic ductal adenocarcinoma (PDAC) metastasis to liver, we studied key molecules involved in this progress and their translational values. Pre-metastatic niche (PMN) and macro metastatic niche (MMN) formation in mouse model were recognized via CT combined 3D organ reconstruction bioluminescence imaging. We next confirmed the expressions and distributions of SLIT2 and ROBO1 in 35 cases of human matched liver metastasis and primary PDAC samples, 14 case human PDAC liver metastasis transcriptional analysis, intrasplenic mouse models and KrasG12D/Trp53R172H/Pdx1-Cre (KPC) mouse models. Translational value was assessed on Slit2fl/fl/Alb1-Cre (Slit2 CKO) mice, KPC mouse model and Ex vivo tests via administration of neutralizing antibody targeting ROBO1. We also analyzed prognosis of 266 cases human PDAC tissue with or without SLIT2-ROBO1 fostered co-evolution and demonstrated the dependence receptor (DR) characteristics of ROBO1 in the following-up mechanism study. Experiments on Slit2 CKO, Slit2 CKO-RE and KPC mouse models demonstrated that disturbing SLIT2-ROBO1 mediated co-evolution in liver microenvironment via preventing their interaction could significantly attenuate liver metastasis of PDAC. We have demonstrated that co-evolution took advantage of DR characteristics in PMN and MMN. Targeting SLIT2-ROBO1 axis could be a therapeutic strategy towards metastatic PDAC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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