Identification of SPP1+ macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer
Yizhou Wang, Qing Wang, Shuangfen Tao, Haoyu Li, Xiaofeng Zhang, Yong Xia, Yue Wang, Cheng Yang, Chengjun Sui
Abstract
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 stemness through a VTN-dependent paracrine mechanism. VTN derived from SPP1 + macrophages could mediate stem transcript factor SOX4 upregulation through integrin αvβ5/AMPK/YAP1signaling, facilitating liver tumor stemness and progression. In tumor, CCL15 derived from liver cancer cells could drive polarization of M0 macrophages toward an SPP1 + macrophage phenotype, thereby establishing a positive feedback loop between SPP1 + macrophages and liver cancer cells. • SPP1+ macrophages regulate tumor stemness in liver cancer. • VTN from SPP1+ macrophages promote integrin αvβ5/AMPK/YAP1/SOX4 signal. • CCL15 by cancer cells drives M0 macrophages polarization toward an SPP1+ macrophage phenotype. • SPP1+ macrophages confer chemoresistance in liver cancer.