Tumor-secreted PAI-1 promotes breast cancer metastasis via the induction of adipocyte-derived collagen remodeling

Xiaohui Wei,Meixiao Zhan,Yang Liu,Wei Yu,Jinyong He,Shengtao Yuan,Chenfei Wang,Li Sun,Hongyang Li,Lifei Han,Ligong Lu,Xin Shi,Sijing Li,Hongzhi Du,Haolin Hu

doi:10.1186/s12964-019-0373-z

Abstract

BackgroundBreast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. However, the role of adipocyte-derived collagen on breast cancer progression still remains unclear.MethodsAdipocytes were cocultured with breast cancer cells for 3D collagen invasion and collagen organization exploration. Breast cancer cells and adipose tissue co- implanted mouse model, clinical breast cancer samples analysis were used to study the crosstalk between adipose and breast cancer cells in vivo. A combination of proteomics, enzyme-linked immunosorbent assay, loss of function assay, qPCR, western blot, database analysis and chromatin immunoprecipitation assays were performed to study the mechanism mediated the activation of PLOD2 in adipocytes.ResultsIt was found that CAAs remodeled collagen alignment during crosstalk with breast cancer cells in vitro and in vivo, which further promoted breast cancer metastasis. Tumor-derived PAI-1 was required to activate the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in CAAs. Pharmacologic blockade of PAI-1 or PLOD2 disrupted the collagen reorganization in CAAs. Mechanistically, it was observed that PI3K/AKT pathway was activated in adipocytes upon co-culturing with breast cancer cells or treatment with recombinant PAI-1, which could promote the translocation of transcription factor FOXP1 into the nucleus and further enhanced the promoter activity of PLOD2 in CAAs. In addition, collagen reorganization at the tumor-adipose periphery, as well as the positive relevance between PAI-1 and PLOD2 in invasive breast carcinoma were confirmed in clinical specimens of breast cancer.ConclusionIn summary, our findings revealed a new stromal collagen network that favors tumor invasion and metastasis establish between breast cancer cells and surrounding adipocytes at the tumor invasive front, and identified PLOD2 as a therapeutic target for metastatic breast cancer treatment.

Highlights

Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis
Breast cancer cells promote adipocyte-derived collagen I reorganization in vitro Several studies have reported that cancer cells can induce dedifferentiation of mature adipocytes into fibroblast-like cells
We showed that adipocytes cocultivated in the presence of breast cancer cells with different invasive capacities exhibited a decrease in the number and size of lipid droplets (Fig. 1a), which was accompanied by a dramatic reduction of the adipogenic markers, including AP2, PPAR-γ and C/EBP-α (Fig. 1b)

Summary

Introduction

Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel collagen and promote tumor metastasis. Adipocytes are the most abundant stromal partners in breast tissue, local invasion of breast cancer leads to the proximity of cancer cells and adipocytes, which respond to generate cancer-associated adipocytes (CAAs). These cells exhibit enhanced secretion of extracellular matrix related proteins, including collagens. The aligned collagen orientation predicts poor patient survival [3, 4], since tumor cells tend to migrate along aligned stromal collagen fibers in breast cancer [5]. As a major source of collagen, cancer-associated fibroblasts (CAFs) have been shown to generate aligned collagen fibers by activating of PLOD2, and silencing PLOD2 in CAFs results in a major effect on collagen fiber formation and linear organization, which further abrogates collagen-induced directed cell migration [8, 9]

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Results

Discussion

Conclusion