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. CD10⁺GPR77⁺ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10⁺GPR77⁺ 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, CD10⁺GPR77⁺ 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 CD10⁺GPR77⁺ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

中文翻译：

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CD10 + GPR77 +与癌症相关的成纤维细胞通过维持癌的形成来促进癌的形成和化学抗性。

癌相关的成纤维细胞（CAF）在肿瘤微环境中是大量且异质的基质细胞，与癌症的进展密切相关。在这里，我们证明了两个细胞表面分子CD10和GPR77特别定义了与乳腺癌和肺癌患者的多个队列中的化学抗药性和较差的生存率相关的CAF子集。CD10 ⁺ GPR77 ⁺ CAF通过为癌症干细胞（CSC）提供生存位来促进肿瘤形成和化学抗药性。从机理上讲，CD10 ⁺ GPR77 ⁺ CAF受p65磷酸化和乙酰化的持续性NF-κB活化作用驱动，而活化作用则通过C5a受体GPR77的补体信号传导得以维持。此外，CD10 ⁺ GPR77⁺ CAF可以促进患者源异种移植物（PDXs）的成功植入，并且以中和性抗GPR77抗体靶向这些CAF可以消除肿瘤的形成并恢复肿瘤的化学敏感性。我们的研究揭示了可以通过特定的细胞表面标志物定义和分离的功能性CAF子集，并表明靶向CD10 ⁺ GPR77 ⁺ CAF子集可能是针对CSC驱动的实体瘤的有效治疗策略。