Single-cell protein activity analysis reveals aberrant myogenesis and IGF2-PI3K pathway dependencies in MYOD1-mutant rhabdomyosarcoma - PubMed
5 hours ago
- #IGF2-PI3K pathway
- #single-cell analysis
- #rhabdomyosarcoma
- Single-cell protein activity analysis identifies aberrant myogenesis and IGF2-PI3K pathway dependencies in MYOD1-mutant rhabdomyosarcoma.
- MYOD1L122R-mutant spindle cell rhabdomyosarcoma (SRMS) is a rare, treatment-resistant sarcoma with poor outcomes.
- Regulatory network analysis of single-nucleus RNA sequencing (snRNA-seq) from six patient tumors reveals disrupted myogenesis and actionable master regulator dependencies across three tumor cell states.
- Three coexisting tumor cell states identified: MYOD1-enriched progenitor-like state, proliferative transition state, and partially differentiated state with reduced MYOD1 activity.
- Ligand-receptor analysis uncovers paracrine IGF2-IGF1R-PI3K signaling from progenitor to transition/differentiated states, with therapeutic potential demonstrated in ex vivo drug screens.
- Inhibition of IGF2-PI3K signaling significantly improved disease control in a patient-derived xenograft model.
- Oncogenic master regulators were recapitulated in 24 bulk RNA profiles, while 20 DNA profiles revealed recurrent IGF2/PI3K/AKT alterations.
- Findings suggest IGF1R-PI3K/AKT/mTOR inhibitors as potential therapeutic options for MYOD1L122R-mutant SRMS.
- Highlights the utility of single-cell regulatory network analysis for uncovering actionable dependencies in rare, transcriptionally complex cancers.