Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Cell. 2018 Feb 8;172(4):841-856.e16. doi: 10.1016/j.cell.2018.01.009. Epub 2018 Jan 25.
Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10GPR77 CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10GPR77 CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10GPR77 CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10GPR77 CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.
癌相关成纤维细胞（CAFs）是肿瘤微环境中丰富且异质性的基质细胞，在癌症进展中起着至关重要的作用。在这里，我们证明了两个细胞表面分子，CD10 和 GPR77，能够特异性地定义一个与乳腺癌和肺癌患者多个队列中的化疗耐药性和不良预后相关的 CAF 亚群。CD10GPR77 CAF 通过为癌症干细胞（CSC）提供生存龛，促进肿瘤形成和化疗耐药性。在机制上，CD10GPR77 CAF 通过 p65 磷酸化和乙酰化持续激活 NF-κB，通过 GPR77 维持补体信号，GPR77 是 C5a 受体。此外，CD10GPR77 CAF 促进了患者来源异种移植（PDX）的成功植入，并用中和抗 GPR77 抗体靶向这些 CAF 可消除肿瘤形成并恢复肿瘤化疗敏感性。我们的研究揭示了一个可通过特定细胞表面标志物定义和分离的功能性 CAF 亚群，并表明靶向 CD10GPR77 CAF 亚群可能是一种针对 CSC 驱动的实体瘤的有效治疗策略。
