Evidence of steady-state fibroblast subtypes in the normal human breast as cells-of-origin for perturbed-state fibroblasts in breast cancer

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-01-16 DOI:10.1186/s13058-024-01763-3
Mikkel Morsing Bagger, Jonas Sjölund, Jiyoung Kim, Katharina Theresa Kohler, René Villadsen, Abbas Jafari, Moustapha Kassem, Kristian Pietras, Lone Rønnov-Jessen, Ole William Petersen
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Abstract

Human breast cancer most frequently originates within a well-defined anatomical structure referred to as the terminal duct lobular unit (TDLU). This structure is endowed with its very own lobular fibroblasts representing one out of two steady-state fibroblast subtypes—the other being interlobular fibroblasts. While cancer-associated fibroblasts (CAFs) are increasingly appreciated as covering a spectrum of perturbed states, we lack a coherent understanding of their relationship—if any—with the steady-state fibroblast subtypes. To address this, we here established two autologous CAF lines representing inflammatory CAFs (iCAFs) and myofibroblast CAFs (myCAFs) and compared them with already established interlobular- and lobular fibroblasts with respect to their origin and impact on tumor formation. Primary breast tumor-derived CAFs were transduced to express human telomerase reverse transcriptase (hTERT) and sorted into CD105low and CD105high populations using fluorescence-activated cell sorting (FACS). The two populations were tested for differentiation similarities to iCAF and myCAF states through transcriptome-wide RNA-Sequencing (RNA-Seq) including comparison to an available iCAF-myCAF cell state atlas. Inference of origin in interlobular and lobular fibroblasts relied on RNA-Seq profiles, immunocytochemistry and growth characteristics. Osteogenic differentiation and bone formation assays in culture and in vivo were employed to gauge for origin in bone marrow-derived mesenchymal stem cells (bMSCs). Functional characteristics were assessed with respect to contractility in culture and interaction with tumor cells in mouse xenografts. The cells’ gene expression signatures were tested for association with clinical outcome of breast cancer patients using survival data from The Cancer Genome Atlas database. We demonstrate that iCAFs have properties in common with interlobular fibroblasts while myCAFs and lobular fibroblasts are related. None of the CAFs qualify as bMSCs as revealed by lack of critical performance in bone formation assays. Functionally, myCAFs and lobular fibroblasts are almost equally tumor promoting as opposed to iCAFs and interlobular fibroblasts. A myCAF gene signature is found to associate with poor breast cancer-specific survival. We propose that iCAFs and myCAFs originate in interlobular and lobular fibroblasts, respectively, and more importantly, that the tumor-promoting properties of lobular fibroblasts render the TDLU an epicenter for breast cancer evolution.
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证明正常人乳房中的稳态成纤维细胞亚型是乳腺癌中扰动态成纤维细胞的起源细胞
人类乳腺癌最常起源于一个定义明确的解剖结构,即末端导管小叶单元(TDLU)。这种结构具有自己的小叶成纤维细胞,是两种稳态成纤维细胞亚型中的一种,另一种是小叶间成纤维细胞。尽管人们越来越认识到癌症相关成纤维细胞(CAFs)涵盖了一系列紊乱状态,但我们对它们与稳态成纤维细胞亚型之间的关系缺乏一致的认识。为了解决这个问题,我们在这里建立了两个自体CAF品系,分别代表炎性CAFs(iCAFs)和肌成纤维细胞CAFs(myCAFs),并就它们的来源和对肿瘤形成的影响与已经建立的小叶间成纤维细胞和小叶成纤维细胞进行了比较。原发性乳腺肿瘤来源的 CAFs 经转导后表达人端粒酶逆转录酶(hTERT),并使用荧光激活细胞分拣(FACS)技术将其分拣为 CD105 低和 CD105 高两种群体。通过全转录组RNA测序(RNA-Seq),包括与现有的iCAF-myCAF细胞状态图谱进行比较,检测这两个群体与iCAF和myCAF状态的分化相似性。根据 RNA-Seq 图谱、免疫细胞化学和生长特征推断球间和小叶成纤维细胞的起源。骨髓间充质干细胞(bMSCs)采用了培养和体内成骨分化和骨形成试验来判断来源。对培养过程中的收缩性以及在小鼠异种移植中与肿瘤细胞相互作用的功能特性进行了评估。利用癌症基因组图谱数据库中的生存数据,测试了细胞的基因表达特征与乳腺癌患者临床结果的关联。我们证明,iCAFs 与小叶间成纤维细胞具有共同特性,而 myCAFs 与小叶成纤维细胞具有相关性。由于在骨形成试验中缺乏关键性能,因此没有一种 CAFs 符合 bMSCs 的条件。在功能上,myCAFs 和小叶成纤维细胞与 iCAFs 和小叶间成纤维细胞相比,几乎同样具有肿瘤促进作用。研究发现,myCAF基因特征与乳腺癌特异性生存率低有关。我们认为,iCAFs 和 myCAFs 分别起源于小叶间成纤维细胞和小叶成纤维细胞,更重要的是,小叶成纤维细胞的肿瘤促进特性使 TDLU 成为乳腺癌演变的中心。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
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发文量
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期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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