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VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Sarah Watson1, Collette A LaVigne2, Lin Xu3

  • 1Institut Curie Research Center, Paris Sciences et Lettres (PSL) Research University, INSERM U830, 75005 Paris, France; Institut Curie, Paris Sciences et Lettres (PSL) Research University, Medical Oncology Department, 75005 Paris, France.

Cell Reports
|January 19, 2023
PubMed

Insights

The VGLL2-NCOA2 gene fusion drives infantile rhabdomyosarcoma by activating developmental pathways. Targeting ARF6, a key player in these pathways, presents a potential therapeutic strategy for sarcomas.

Area of Science:

  • Oncology
  • Genetics
  • Developmental Biology

Background:

  • Clinical sequencing identifies numerous sarcoma gene fusions lacking functional validation.
  • The VGLL2-NCOA2 fusion, observed in infantile rhabdomyosarcoma, exemplifies such a fusion.
  • Understanding the functional role of VGLL2-NCOA2 is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the tumorigenic mechanisms of the VGLL2-NCOA2 fusion.
  • To identify potential therapeutic vulnerabilities associated with VGLL2-NCOA2.
  • To utilize a cross-species comparative oncology approach for comprehensive analysis.

Main Methods:

  • Employing zebrafish models for functional studies of VGLL2-NCOA2.
  • Utilizing mouse allograft models to assess tumor development and recapitulation of human disease.
  • Analyzing patient samples to validate findings from preclinical models.
  • Performing transcriptional profiling of tumors to identify associated developmental programs.

Main Results:

  • VGLL2-NCOA2 is sufficient to induce mesenchymal tumors with immature skeletal muscle features, mirroring human rhabdomyosarcoma.
  • Transcriptional analysis revealed VGLL2-NCOA2 tumors engage embryonic somitogenesis and developmental programs, including the RAS family GTPase ARF6.
  • ARF6 demonstrated high expression across zebrafish, mouse, and patient-derived tumors.
  • ARF6 knockout inhibited VGLL2-NCOA2's oncogenic activity in vitro, and ARF6 overexpression was noted in various pediatric and adult sarcomas.

Conclusions:

  • VGLL2-NCOA2 functions as an oncogene by hijacking developmental programs for tumor formation.
  • The reactivation or persistent expression of ARF6 represents a significant therapeutic vulnerability in sarcomas driven by VGLL2-NCOA2.
  • Targeting ARF6 may offer a novel therapeutic strategy for patients with specific sarcoma subtypes.
Keywords:
CP: Cancercross-species comparative oncologydevelopmental biologyfunctional genomicsfusion oncogenepediatric cancerrhabdomyosarcoma

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