Research Paper|Volume 13, Issue 3|pp 3386—3404

Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition

Cheng Xiong^1,^2,^3,⁴, Youwei Zhu^1,^2,^3,⁴, Meilin Xue^1,^2,^3,⁴, Yongsheng Jiang^1,^2,^3,⁴, Yiming Zhong^1,^2,^3,⁴, Lingxi Jiang^1,^2,^3,⁴, Minmin Shi^1,^2,^3,⁴, Hao Chen^1,^2,^3,⁴

¹Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
²Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
³State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
⁴Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China

* Equal contribution

Received: April 16, 2020Accepted: September 28, 2020Published: January 10, 2021

https://doi.org/10.18632/aging.202264

Copyright: © 2021 Xiong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68⁺ TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis in the TAM-CM treatment group than the controls. H&E staining of liver tissues showed significantly higher numbers of metastatic nodules in the TAM-CM treatment group. Heat inactivation of TAM-CM significantly reduced Transwell migration by PDAC cells, suggesting the involvement of one or more secreted proteins in PDAC progression. Transcriptome sequencing analysis of PDAC cells treated with TAM-CM revealed significant enrichment of transforming growth factor-β (TGF-β) signaling pathway genes. Western blot and qRT-PCR analysis showed that TAM-CM enhanced PDAC migration cells by inducing epithelial-to-mesenchymal transition through the TGF-β-Smad2/3/4-Snail signaling axis. The pro-tumorigenic effects of TAMs or TAM-CM were abolished by TGF-β signaling pathway inhibitors and neutralizing TGF-β antibody. These results demonstrate that TAMs promote PDAC progression through the TGF-β signaling pathway.