Landscape of cancer-associated fibroblasts identifies the secreted biglycan as a protumor and immunosuppressive factor in triple-negative breast cancer

OncoImmunology

Weikai Xiao¹  Lu Yang¹  Weidong Wei²  Anli Yang²  Linyu Wu²  Xinhua Xie²  Shaoquan Zheng²  Yutian Zou²  Jie-Ying Liang²  Wenwen Tian²  Jindong Xie²  Xiaoming Xie²  Yuhui Tang² 

[1] Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences;Sun Yat-sen University Cancer Center;

关键词: triple-negative breast cancer;    cancer-associated fibroblast;    biglycan;    immune microenvironment;    extracellular matrix;   

DOI  :  10.1080/2162402X.2021.2020984

来源: DOAJ

【 摘 要 】

Cancer-associated fibroblasts (CAFs) are essential for tumor microenvironment remodeling and correlate with tumor progression. However, interactions between CAFs and tumor cells and immune cells in triple-negative breast cancer (TNBC) are still poorly explored. Here, we investigate the role of CAFs in TNBC and potential novel mediators of their functions. The clustering of classic markers was applied to estimate the relative abundance of CAFs in TNBC cohorts. Primary fibroblasts were isolated from normal and tumor samples. The RNA and culture medium of fibroblasts were subjected to RNA sequencing and mass spectrometry to explore the upregulated signatures in CAFs. Microdissection and single-cell RNA sequencing datasets were used to examine the expression profiles. CAFs were associated with hallmark signalings and immune components in TNBC. Clustering based on CAF markers in the literature revealed different CAF infiltration groups in TNBC: low, medium and high. Most of the cancer hallmark signaling pathways were enriched in the high CAF infiltration group. Furthermore, RNA sequencing and mass spectrometry identified biglycan (BGN), a soluble secreted protein, as upregulated in CAFs compared to normal cancer-adjacent fibroblasts (NAFs). The expression of biglycan was negatively correlated with CD8 + T cells. Biglycan indicated poor prognostic outcomes and might be correlated with the immunosuppressive tumor microenvironment (TME). In conclusion, CAFs play an essential role in tumor progression and the TME. We identified an extracellular protein, biglycan, as a prognostic marker and potential therapeutic target in TNBC.

【 授权许可】

Unknown