Hijacking tumour cells to bring them back onto the right track

 Dr. Sara Danielli

University Children's Hospital Zurich

Rhabdomyosarcoma (RMS) is a tumour originating from the muscle lineage, and the most common soft tissue cancer in children and adolescents. Its most aggressive form alveolar RMS (aRMS) is refractory to surgery and treatments, and in critical need for effective therapeutic approaches. Traditionally, RMS cells have been characterized in bulk, which is limited to measuring only the average signal within a complex population. As one of the greatest barriers to successful anticancer treatment is intratumoral heterogeneity, understanding the composition of RMS tumours cell by cell could help identifying better treatments.

The scientists showed that aRMS tumours contain a majority of aggressive cells resembling immature developing muscles, but also a minority of cells that resembles more mature and differentiated muscle fibres, i.e. cells that have lost their ability to proliferate. In patients with better outcomes, the differentiated ”good“ muscle-like cells were enriched. They therefore identified a combination of drugs that initiate cellular differentiation in aRMS tumours, and thereby inhibits the growth of the cancer cells. 

Sara Danielli and her team, unraveled the single-cell composition of pediatric RMS. They devised a novel drug-based treatment approach that forces the tumour cells to differentiate and thereby slows down their growth. With other words: They discovered for the first time that alveolar RMS can be treated not only by chemotherapy, but also by directing their tumour circuit from aggressive subpopulations into less malignant differentiated cells using drugs that are already under clinical evaluation.

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance. Sara G. Danielli, Ermelinda Porpiglia, Andrea J. De Micheli, Natalia Navarro, Michael J. Zellinger, Ingrid Bechtold, Samanta Kisele, Larissa Volken, Joana G. Marques, Stephanie Kasper, Peter K. Bode, Anton G. Henssen, Dennis Gürgen, Olivier Delattre, Didier Surdez, Josep Roma, Peter Bühlmann, Helen M. Blau, Marco Wachtel, Beat W. Schäfer.  Sci Adv. 2023 Feb 10;9(6):eade9238