Related Experiment Video

Updated: Mar 1, 2026

Identification of MyoD Interactome Using Tandem Affinity Purification Coupled to Mass Spectrometry
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Identification of MyoD Interactome Using Tandem Affinity Purification Coupled to Mass Spectrometry

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Single-cell protein activity analysis reveals aberrant myogenesis and IGF2-PI3K pathway dependencies in MYOD1-mutant

Josephine K Dermawan1, Fabio Vanoli2, Henry Traux de Wardi3

  • 1Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.

Science Advances
|February 27, 2026
PubMed

Insights

We identified a key signaling pathway involving insulin-like growth factor 2 (IGF2) that drives rare spindle cell rhabdomyosarcoma (SRMS). Inhibiting this pathway shows promise for treating this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Myogenic differentiation 1 (MYOD1)L122R-mutant spindle cell rhabdomyosarcoma (SRMS) is an extremely rare and treatment-resistant cancer with poor outcomes.
  • Understanding the underlying molecular mechanisms and identifying therapeutic targets is crucial for improving patient prognosis.

Purpose of the Study:

  • To analyze regulatory networks in MYOD1-mutant SRMS to identify actionable therapeutic vulnerabilities.
  • To investigate the role of specific signaling pathways in tumor cell state maintenance and progression.

Main Methods:

  • Single-nucleus RNA sequencing (snRNA-seq) was performed on six patient tumors.
  • Regulatory network analysis and ligand-receptor interaction analysis were employed.
  • Ex vivo drug screens and patient-derived xenograft (PDX) models were used to test therapeutic potential.

Main Results:

  • Three distinct tumor cell states were identified: MYOD1-enriched progenitor-like, proliferative transition, and partially differentiated.
  • Paracrine insulin-like growth factor 2 (IGF2)-IGF1 receptor (IGF1R)-phosphatidylinositol 3-kinase (PI3K) signaling was found to be crucial.
  • Inhibition of IGF1R-PI3K/AKT/mTOR signaling demonstrated therapeutic efficacy in preclinical models.

Conclusions:

  • Aberrant MYOD1-driven myogenesis, sustained by IGF2 signaling, characterizes MYOD1L122R-mutant SRMS.
  • IGF1R-PI3K/AKT/mTOR pathway inhibitors are nominated as potential therapeutics for this rare sarcoma.
  • Single-cell regulatory network analysis is a powerful tool for uncovering therapeutic targets in complex cancers.

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