Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer
Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer
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DOI：
10.3390/cancers12051307
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发表时间：
2020-05-01
期刊：
影响因子：
5.2
通讯作者：
Loots, Gabriela G.
中科院分区：
文献类型：
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作者：
Sebastian, Aimy;Hum, Nicholas R.;Loots, Gabriela G.
肿瘤相关成纤维细胞(CAF)是实体瘤中一种重要的间质细胞类型，其分泌的分子在肿瘤的进展和转移中起重要作用。CAF作为具有潜在不同生物学功能的异质种群共存。虽然CAF是乳腺癌间质的主要成分，但CAF在乳腺癌中的分子和表型异质性还知之甚少。在这项研究中，我们研究了三阴性乳腺癌(TNBC)中CAF的异质性，使用的是同基因小鼠模型BALB/c来源的4T1乳腺肿瘤。使用单细胞RNA测序(scRNA-seq)，我们在4T1肿瘤中鉴定出六个CAF亚群，包括：1)肌成纤维细胞CAF，富含α-平滑肌肌动蛋白和其他几种收缩蛋白；2)炎症性CAF，炎性细胞因子表达升高；3)CAF亚群表达主要组织相容性复合体(MHC)II类蛋白，通常在抗原提呈细胞中表达。比较4T1来源的CAF和来自胰腺癌的CAF，发现这三个CAF亚群在两种肿瘤类型中都存在。有趣的是，在正常的乳腺/胰腺组织中也检测到炎性细胞和表达MHC-II类的CAF，这表明这些表型不是肿瘤微环境诱导的。这项工作加深了我们对CAF异质性的理解，针对这些CAF亚群可能是治疗高度侵袭性TNBCs的有效治疗方法。
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 alpha -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.