Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer

• Published in: Cancers Vol. 12; no. 5; p. 1307
• Main Authors: Sebastian, Aimy, Hum, Nicholas R, Martin, Kelly A, Gilmore, Sean F, Peran, Ivana, Byers, Stephen W, Wheeler, Elizabeth K, Coleman, Matthew A, Loots, Gabriela G
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.05.2020; MDPI
• Subjects: 60 APPLIED LIFE SCIENCES; Actin; Antigen-presenting cells; Breast cancer; CAF heterogeneity; Cancer therapies; cancer-associated fibroblasts; Cell adhesion & migration; Cytokines; Enzymes; Extracellular matrix; Fibroblasts; Gene expression; gene expression profiling; Genomics; Growth factors; Inflammation; inflammatory fibroblasts; Major histocompatibility complex; mammary fat pad; Metastases; Muscle contraction; myofibroblasts; normal fibroblasts; Pancreatic cancer; Phenotypes; Proteins; Ribonucleic acid; RNA; scRNA-seq; Smooth muscle; Solid tumors; Stem cells; Tumors; CAF heterogeneity; mammary fat pad; cancer-associated fibroblasts; pancreatic cancer; scRNA-seq; inflammatory fibroblasts; breast cancer; gene expression profiling; myofibroblasts; normal fibroblasts
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12051307

Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as heterogeneous populations with potentially different biological functions. Although CAFs are a major component of the breast cancer stroma, molecular and phenotypic heterogeneity of CAFs in breast cancer is poorly understood. In this study, we investigated CAF heterogeneity in triple-negative breast cancer (TNBC) using a syngeneic mouse model, BALB/c-derived 4T1 mammary tumors. Using single-cell RNA sequencing (scRNA-seq), we identified six CAF subpopulations in 4T1 tumors including: 1) myofibroblastic CAFs, enriched for α-smooth muscle actin and several other contractile proteins; 2) 'inflammatory' CAFs with elevated expression of inflammatory cytokines; and 3) a CAF subpopulation expressing major histocompatibility complex (MHC) class II proteins that are generally expressed in antigen-presenting cells. Comparison of 4T1-derived CAFs to CAFs from pancreatic cancer revealed that these three CAF subpopulations exist in both tumor types. Interestingly, cells with inflammatory and MHC class II-expressing CAF profiles were also detected in normal breast/pancreas tissue, suggesting that these phenotypes are not tumor microenvironment-induced. This work enhances our understanding of CAF heterogeneity, and specifically targeting these CAF subpopulations could be an effective therapeutic approach for treating highly aggressive TNBCs.