Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells

Jin Gong,Chunqi Liu,Xiao Du,Huaqin Zhang,Xinying Qian,Xiaobo Cen,Zhong Cheng,Yuanyuan Xiao,Liang Wang,Xiaowei Yang,Yiyun Lin,Jiamei Zhang,Yinglan Zhao,Na Sang

doi:10.1038/s41419-020-2434-z

Abstract

Metabolic interaction between cancer-associated fibroblasts (CAFs) and colorectal cancer (CRC) cells plays a major role in CRC progression. However, little is known about lipid alternations in CAFs and how these metabolic reprogramming affect CRC cells metastasis. Here, we uncover CAFs conditioned medium (CM) promote the migration of CRC cells compared with normal fibroblasts CM. CAFs undergo a lipidomic reprogramming, and accumulate more fatty acids and phospholipids. CAFs CM after protein deprivation still increase the CRC cells migration, which suggests small molecular metabolites in CAFs CM are responsible for CRC cells migration. Then, we confirm that CRC cells take up the lipids metabolites that are secreted from CAFs. Fatty acids synthase (FASN), a crucial enzyme in fatty acids synthesis, is significantly increased in CAFs. CAF-induced CRC cell migration is abolished by knockdown of FASN by siRNA or reducing the uptake of fatty acids by CRC cells by sulfo-N-succinimidyloleate sodium in vitro and CD36 monoclonal antibody in vivo. To conclude, our results provide a new insight into the mechanism of CRC metastasis and suggest FASN of CAFs or CD36 of CRC cells may be potential targets for anti-metastasis treatment in the future.

Highlights

Colorectal cancer (CRC), the third most commonly diagnosed malignant cancer, ranks third in cancer mortality worldwide[1]
Characterization of primary normal fibroblasts (NFs) and Cancer-associated fibroblasts (CAFs) The abundances of fibroblasts in tumor microenvironment (TME) were confirmed by immunohistochemistry (IHC) staining of α-SMA, and the results showed that high density of α-SMA expression were observed in CRC tissues than that in normal adjacent tissues (NATs), which suggest that fibroblasts is more abundance in CRC tissues (Fig. 1a)
Immunofluorescence results showed that Vimentin and α-SMA expression was positive, whereas cytokeratin expression was negative in NFs and CAFs (Fig. 1c), which suggesting pure fibroblasts were obtained

Summary

Introduction

Colorectal cancer (CRC), the third most commonly diagnosed malignant cancer, ranks third in cancer mortality worldwide[1]. Recent studies illustrate that tumor metastasis is closely depended on the interaction of tumor cells with tumor microenvironment (TME), which is a dynamic, changing network. CAFs are active fibroblasts that proliferate faster, and secrete more cytokines, matrix proteins, and immunomodulatory factors compared with normal fibroblasts (NFs)[2,3,4]. It is established that CAFs play an indispensable role in tumor initiation, progression, and metastasis mainly by remodeling of the extracellular matrix (ECM), induction of angiogenesis, secretion growth factors and cytokines, and promoting epithelial mesenchymal transition (EMT)[5]. CAFs lead tumor growth and metastasis via cytokine and microRNA interactions[5]. Recent works reveal the impact of metabolic interaction between CAFs and tumor cells on tumor metastasis

Methods

Results

Conclusion