Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with...

Area of Science:

• Oncology
• Developmental Biology
• Genetics

Background:

• Rhabdomyosarcoma (RMS) is a pediatric cancer originating from skeletal muscle precursors.
• The cellular dynamics and developmental pathways driving RMS progression are not fully understood.
• Alveolar RMS (aRMS) is an aggressive subtype with significant unmet therapeutic needs.

Purpose of the Study:

• To elucidate the cellular heterogeneity and developmental states within patient-derived aRMS.
• To identify therapeutic strategies targeting chemoresistant subpopulations in aRMS.
• To investigate the role of the RAS pathway in aRMS aggressiveness and progression.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) to analyze gene expression profiles.
• Mass cytometry (CyTOF) for high-dimensional immune cell profiling.
• High-content imaging to assess cellular morphology and function.
• Drug screening to identify novel therapeutic agents.

Main Results:

• aRMS exhibits a hierarchy including plastic muscle stem-like cells and cycling progenitors, alongside differentiated cells associated with better outcomes.
• Chemotherapy effectively targets cycling progenitors but enriches for stem-like cells, contributing to relapse.
• A combination of RAF and MEK inhibitors was identified to induce myogenic differentiation and inhibit tumor growth.

Conclusions:

• Understanding aRMS intratumoral heterogeneity is crucial for developing effective treatments.
• The RAS pathway represents a promising therapeutic target for aRMS.
• Targeting specific developmental states offers a novel strategy to overcome chemoresistance and improve outcomes in pediatric rhabdomyosarcoma.