Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice we determined that CAFs in both invasive lobular breast cancer and triple negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo tracing and in vitro studies revealed the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. In vitro functional assays showed that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data show that CD26+ and CD26- NFs transform into distinct CAF subpopulations in breast cancer.

中文翻译：

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CD26 阴性和 CD26 阳性组织驻留成纤维细胞有助于乳腺癌中功能不同的 CAF 亚群

癌症相关成纤维细胞 (CAF) 大量存在于几乎所有肿瘤的微环境中，并强烈影响肿瘤进展。尽管对其功能和异质性的了解越来越多，但对 CAF 的起源知之甚少。需要了解 CAF 异质性的起源以开发成功的基于 CAF 的靶向治疗。通过对小鼠的各种移植研究，我们确定侵袭性小叶乳腺癌和三阴性乳腺癌中的 CAF 均源自乳腺组织驻留的正常成纤维细胞 (NF)。单细胞转录组学、体内追踪和体外研究揭示了 CD26+ 和 CD26- NF 种群分别转变为炎性 CAF (iCAF) 和肌纤维母细胞 CAF (myCAF)。体外功能测定表明，CD26+ NFs 转变为促肿瘤 iCAFs，其以 CXCL12 依赖性方式募集骨髓细胞并通过基质金属蛋白酶 (MMP) 活性增强肿瘤细胞侵袭。总之，我们的数据表明，CD26+ 和 CD26- NFs 在乳腺癌中转化为不同的 CAF 亚群。