Formononetin Antagonizes Osteosarcoma Metastasis by Targeting CD44: An Integrated Multi-Omics Study
Wenyu Feng1, Wei Dai2, Gejin Wei3
1Department of Bone and Joint Diseases Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, China; Pharmaceutical College, Guangxi Medical University, Nanning 530021, China.
Summary
Chemoresistant osteosarcoma (OS) cells promote metastasis through CD44-mediated endothelial dysfunction. The natural compound formononetin (FMN) inhibits this process by targeting CD44, offering a promising therapeutic strategy for metastatic OS.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Metastasis is the primary cause of death in osteosarcoma (OS).
- Chemoresistant OS cell subpopulations drive metastasis, but their mechanisms remain poorly understood.
- Identifying effective drugs targeting these cells is a major challenge.
Purpose of the Study:
- To identify a chemoresistant, metastasis-prone OS subpopulation.
- To elucidate the pro-metastatic mechanism involving endothelial dysfunction.
- To investigate formononetin (FMN) as a potential inhibitor of this mechanism.
Main Methods:
- Integrated analysis of bulk RNA-seq, scRNA-seq, and spatial transcriptomics data.
- In silico molecular docking and dynamics simulations to predict FMN-CD44 interactions.
- In vitro functional assays (Transwell, migration, co-culture) and in vivo metastasis models.
Main Results:
- A chemoresistant OS cell cluster (TC1) was identified, spatially associated with metastatic endothelial cells (C5).
- CD44 was identified as a critical target mediating TC1-induced endothelial dysfunction.
- Formononetin (FMN) demonstrated stable binding to CD44 and inhibited OS cell migration, invasion, and endothelial barrier disruption both in vitro and in vivo.
Conclusions:
- Chemoresistant OS cells promote metastasis via CD44-mediated endothelial dysfunction.
- Formononetin (FMN) shows significant therapeutic potential by directly inhibiting CD44 and OS cell transendothelial invasion.
- This study provides novel insights into treating metastatic chemoresistant osteosarcoma.
