2. Academic Validation
  3. Clinical characteristics and target exploration via scRNA-seq and high-throughput drug screening of FOXO1 fusion positive rhabdomyosarcoma

Clinical characteristics and target exploration via scRNA-seq and high-throughput drug screening of FOXO1 fusion positive rhabdomyosarcoma

  • Pediatr Surg Int. 2025 Nov 15;42(1):12. doi: 10.1007/s00383-025-06241-1.
Yifei Lu # 1 2,  Tian Xia # 3,  Yongjia Jin # 4,  Yi Li 1 2,  Ran Yang 1 2,  Deqian Chen 1 2,  Yong Chen 5 6,  Yong Zhan 1 2,  Yang Xiang 7,  Zai Song 8 9,  Rui Dong 10 11
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China.
  • 2 Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, 201102, China.
  • 3 Department of Orthopedic & Sports Medicine, Shanghai United Family Hospital, Shanghai, 200335, China.
  • 4 Department of Orthopedics, Shanghai Electric Power Hospital, Shanghai, 200050, China.
  • 5 Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 6 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 7 Department of Orthopedics, Shanghai Electric Power Hospital, Shanghai, 200050, China. [email protected].
  • 8 Department of Pediatric Surgery, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China. [email protected].
  • 9 Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, 201102, China. [email protected].
  • 10 Department of Pediatric Surgery, Children's Hospital of Fudan University at Xiamen, Xiamen, 361006, China. [email protected].
  • 11 Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai, 201102, China. [email protected].
  • # Contributed equally.
PMID: 41240117 DOI: 10.1007/s00383-025-06241-1
Abstract

Purpose: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. FOXO1 fusion indicates poor prognosis and lead to dysregulation of transcriptioanal network. This study aims to investigate clinical characteristics and therapeutic targets concerning FOXO1 fusion status.

Method: 65 pediatric RMS patients were enrolled. Clinical data were analyzed using Kaplan-Meier estimates and COX regression. Surgically resected tumor tissues were subject to single-cell RNA Sequencing (scRNA-seq). Patient-derived xenograft (PDX) was establish and dissociated to cells for high-throughput drug screening.

Results: Among the 65 patinets (36 patients with embryonal RMSs (ERMSs), 15 patients with alveolar RMSs (ARMSs) and 14 patients with Other types of RMSs), 73.3% of ARMSs were defined as fusion positive (FP) while 6 ERMS (ERMS)s were also FP. COX regression analysis identified FOXO1 fusion as a risk factor alone and combined with pathologic subtype, sex and age or metastasis status. scRNA-seq revealed distinct transcription factor networks between FP and FN RMS, showing up-regulated activity of OLIG2, NHLH1, SNAI1, TFF3 and Other TFs related to neural development and differentiation. MAPK, PI3K-Akt, and mTOR pathways were enriched in FP-RMS tumor cells. High-throughput drug screening of PDX-derived cells identified sensitive drugs targeting FP-RMS specific signatures. AMG-337 was selected and validated for its anti-tumor effect.

Conclusion: FOXO1 fusion status influences RMS clinical outcomes, including rare FP-ERMS cases. scRNA-seq combined with drug screening identified MET as a promising therapeutic target in FP-RMS.

Keywords

FOXO1 fusion; High-throughput drug screening; MET inhibitor; Rhabdomyosarcoma; Single-cell RNA sequencing.

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