Identification of SPP1+ macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer

作者：Yizhou Wang, Qing Wang, Shuangfen Tao, Haoyu Li, Xiaofeng Zhang, Yong Xia, Yue Wang, Cheng Yang, Chengjun Sui · 发表于：Cancer Letters · 年份：2024 · DOI：10.1016/j.canlet.2024.217199 · 被引用次数：36 · 研究领域：Immune cells in cancer、Cancer Cells and Metastasis、RNA modifications and cancer

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. SPP1 + macrophages promote tumor ste...