Department of Hepatic Surgery IV, The Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, PR China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, 200438, PR China.
Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, PR China.
Cancer Lett. 2024 Nov 1;604:217199. doi: 10.1016/j.canlet.2024.217199. Epub 2024 Aug 30.
Macrophages play a multifaceted role in cancer biology, with both pro-tumorigenic and anti-tumorigenic functions. Understanding the mechanisms underlying macrophage involvement in cancer progression is essential for the development of therapeutic strategies. Our study analyzed single-cell RNA sequencing data from 12 patients with liver cancer and identified a subpopulation of macrophages characterized by elevated expression of SPP1, which correlates with poor prognosis in liver cancer patients. These SPP1 macrophages induce upregulation of tumor stemness through a vitronectin (VTN)-dependent paracrine mechanism. Mechanistically, VTN derived from SPP1 macrophages promote integrin αvβ5/adenosine 5'-monophosphate-activated protein kinase (AMPK)/Yes-associated protein 1 (YAP1)/SYR-box transcription factor 4 (SOX4) signaling, mediating liver tumor stemness and progression. Conversely, CCL15 produced by liver cancer cells drives polarization of M0 macrophages toward an SPP1 macrophage phenotype, establishing a positive feedback loop of macrophage-tumor stemness. Furthermore, the presence of SPP1 macrophages confers chemoresistance in liver cancer, and inhibition of the macrophage-tumor feedback loop through targeting integrin αvβ5/YAP1 signaling sensitizes liver cancer cells to chemotherapy. Our study highlights the crucial role of SPP1 macrophages in liver cancer progression, providing novel insights for clinical liver cancer therapy.
巨噬细胞在癌症生物学中发挥着多方面的作用，具有促肿瘤和抗肿瘤的功能。了解巨噬细胞参与癌症进展的机制对于开发治疗策略至关重要。我们的研究分析了 12 名肝癌患者的单细胞 RNA 测序数据，鉴定出一群特征为 SPP1 表达上调的巨噬细胞亚群，这与肝癌患者的预后不良相关。这些 SPP1 巨噬细胞通过依赖于纤连蛋白（VTN）的旁分泌机制诱导肿瘤干性的上调。在机制上，源自 SPP1 巨噬细胞的 VTN 促进整合素 αvβ5/腺苷 5'-单磷酸激活蛋白激酶（AMPK）/Yes 相关蛋白 1（YAP1）/SYR 框转录因子 4（SOX4）信号传导，介导肝肿瘤干性和进展。相反，肝癌细胞产生的 CCL15 驱动 M0 巨噬细胞向 SPP1 巨噬细胞表型极化，建立巨噬细胞-肿瘤干性的正反馈回路。此外，SPP1 巨噬细胞的存在赋予肝癌化疗耐药性，通过靶向整合素 αvβ5/YAP1 信号抑制巨噬细胞-肿瘤反馈回路可使肝癌细胞对化疗敏感。我们的研究强调了 SPP1 巨噬细胞在肝癌进展中的关键作用，为临床肝癌治疗提供了新的见解。
