Colorectal cancer-associated fibroblasts promote metastasis by up-regulating LRG1 through stromal IL-6/STAT3 signaling

Beiping Zhong,Zhitong Niu,Yu-Feng Chen,Wenyu Wang,Bing Cheng,Xiao-Jian Wu,Qian Xiao,Xiaoming Huang,Qiang Yu

doi:10.1038/s41419-021-04461-6

Abstract

Cancer-associated fibroblasts (CAFs) have been shown to play a strong role in colorectal cancer metastasis, yet the underlying mechanism remains to be fully elucidated. Using CRC clinical samples together with ex vivo CAFs-CRC co-culture models, we found that CAFs induce expression of Leucine Rich Alpha-2-Glycoprotein 1(LRG1) in CRC, where it shows markedly higher expression in metastatic CRC tissues compared to primary tumors. We further show that CAFs-induced LRG1 promotes CRC migration and invasion that is concomitant with EMT (epithelial-mesenchymal transition) induction. In addition, this signaling axis has also been confirmed in the liver metastatic mouse model which displayed CAFs-induced LRG1 substantially accelerates metastasis. Mechanistically, we demonstrate that CAFs-secreted IL-6 (interleukin-6) is responsible for LRG1 up-regulation in CRC, which occurs through a direct transactivation by STAT3 following JAK2 activation. In clinical CRC tumor samples, LRG1 expression was positively correlated with CAFs-specific marker, α-SMA, and a higher LRG1 expression predicted poor clinical outcomes especially distant metastasis free survival, supporting the role of LRG1 in CRC progression. Collectively, this study provided a novel insight into CAFs-mediated metastasis in CRC and indicated that therapeutic targeting of CAFs-mediated IL-6-STAT3-LRG1 axis might be a potential strategy to mitigate metastasis in CRC.

Highlights

Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer-related death
LRG1 is upregulated in metastatic colorectal cancer, which is associated with cancer-associated fibroblasts To explore the critical mechanisms underlying CRC metastasis promoted by cancer-associated fibroblasts, we firstly isolated Cancer-associated fibroblasts (CAFs) from primary tumors of CRC patients and normal fibroblasts (NFs) from the adjacent normal mucosa of CRC patients as previously reported [22]
Overlapping transcriptomic analysis revealed that 39 genes were up-regulated in both cancer cells co-cultured with CAFs and metastatic tumors compared to primary tumors (Fig. 1a)

Summary

INTRODUCTION

Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer-related death. According to a recently available classification system, CRC can be divided into four consensus molecular subtypes (CMSs), by which CMS4 is characterized by prominent transforming growth factor β activation and stromal invasion. CMS4 is more aggressive and metastatic than other CMSs, indicating an important role of stromal cells in mediating metastasis in CRC [4,5,6,7]. A recent delicate study using single-cell technology combined with high-content digital imaging has demonstrated that the abundance of CAFs was linked with cancer heterogeneity and invasive potential in pancreatic cancer [9]. Overexpression of LRG1 has been found in multiple cancers such as pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer, where it promotes cell proliferation, migration and invasion. There are contradictory findings showing that LRG1 suppresses migration and invasion of esophageal squamous cell carcinoma

Zhong et al 2

RESULTS

DISCUSSION