Single-cell protein activity analysis reveals aberrant myogenesis and IGF2-PI3K pathway dependencies in MYOD1-mutant rhabdomyosarcoma
Menée à l'aide d'organoïdes, de xénogreffes sur des modèles murins, d'échantillons tumoraux d'origine humaine et d'une analyse de l'activité protéique, cette étude met en évidence les facteurs régulateurs du rhabdomyosarcome avec mutation MYOD1L122R ainsi que le rôle du facteur IGF2 et de la voie de signalisation IGF1R-PI3K/AKT/mTOR dans la progression tumorale
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 MYOD1L122R-mutant SRMS, underscoring the utility of single-cell regulatory network analysis for uncovering actionable dependencies in rare, transcriptionally complex cancers. Regulatory network analysis of snRNA-seq in MYOD1L122R-mutant SRMS revealed aberrant differentiation and actionable MRs.
Science Advances , article en libre accès, 2026