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

  • Cancer Lett. 2024 Aug 30:604:217199. doi: 10.1016/j.canlet.2024.217199.
Yizhou Wang  1 ,  Qing Wang  2 ,  Shuangfen Tao  3 ,  Haoyu Li  4 ,  Xiaofeng Zhang  5 ,  Yong Xia  6 ,  Yue Wang  7 ,  Cheng Yang  8 ,  Chengjun Sui  9
Affiliations
  • 1. 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. Electronic address: [email protected].
  • 2. Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, PR China. Electronic address: [email protected].
  • 3. Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, PR China. Electronic address: [email protected].
  • 4. Department of Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, PR China. Electronic address: [email protected].
  • 5. 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. Electronic address: [email protected].
  • 6. 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. Electronic address: [email protected].
  • 7. Department of Stem Cell and Regeneration Medicine, Translational Medicine Research Center, Naval Medical University, Shanghai, 200433, PR China; Department of Histology and Embryology, Basic Medicine Collage, Naval Medical University, Shanghai, 200433, PR China; Shanghai Key Laboratory of Cell Engineering, Shanghai, 200062, PR China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200092, PR China. Electronic address: [email protected].
  • 8. Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, PR China; Shanghai GoBroad Cancer Hospital, China Pharmaceutical University, Shanghai, 200131, PR China. Electronic address: [email protected].
  • 9. Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, PR China. Electronic address: [email protected].
PMID: 39216547 DOI: 10.1016/j.canlet.2024.217199
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.

Keywords
CCL15; Liver cancer; SPP1(+) macrophages; Vitronectin.
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