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Updated: Mar 1, 2026

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

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

Published on: May 17, 2016

Análisis de la actividad proteica unicelular revela miogénesis aberrante y dependencias de la vía IGF2-PI3K en el

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

Abstract:

Myogenic differentiation 1 (MYOD1)^L122R-mutant spindle cell rhabdomyosarcoma (SRMS) is an ultrarare, treatment-resistant sarcoma with dismal outcomes. We performed regulatory network analysis of single-nucleus RNA sequencing (snRNA-seq) from six patient tumors, revealing disrupted myogenesis and actionable master regulator (MR) dependencies across three coexisting tumor cell states, also conserved in patient-derived xenografts: (i) a MYOD1-enriched progenitor-like state, (ii) a proliferative transition state, and (iii) a partially differentiated state with reduced MYOD1 activity. Ligand-receptor analysis uncovered paracrine insulin-like growth factor 2 (IGF2)-IGF1 receptor (IGF1R)-phosphatidylinositol 3-kinase (PI3K) signaling from progenitor to transition/differentiated states, whose inhibition demonstrated therapeutic potential in ex vivo drug screens, and significantly improved disease control in a patient-derived xenograft model. Oncogenic MRs were recapitulated in 24 bulk RNA profiles, while 20 DNA profiles revealed recurrent IGF2/PI3K/AKT alterations, reinforcing shared transcriptional vulnerabilities. These findings characterize aberrant, mutant MYOD1-driven myogenesis sustained by IGF2 and nominate IGF1R-PI3K/AKT/mammalian target of rapamycin inhibitors for therapeutic translation in MYOD1^L122R-mutant SRMS, underscoring the utility of single-cell regulatory network analysis for uncovering actionable dependencies in rare, transcriptionally complex cancers.

Palabras clave:

rabdomiosarcoma MYOD1 células fusiformes IGF2 PI3K terapias dirigidas medicina de precisión

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