Cellular and molecular drivers of PAX3:FOXO1-positive rhabdomyosarcoma initiation and maintenance

• Applicant: Professorin Dr. Simone Hettmer
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology ; Cell Biology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290640517

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, comprises a diverse group of cancers. Fusion-positive RMS (F+RMS) is a distinct RMS subtype associated with the presence of exclusive chromosomal translocations of the PAX3 or PAX7 genes to the transactivation domain of the FOXO1 gene and very poor prognosis. Identifying new strategies to improve RMS treatment is an important, unmet clinical need in pediatric oncology.This proposed research will examine the network of cellular and molecular events that drive the initiation (aim 1) and maintenance (aim 2) of F+RMS expressing PAX3:FOXO1. Tumor initiation is the process by which normal cells acquire genetic changes and turn into cancer cells, whereas tumor maintenance refers to the mechanisms that allow these cells to survive and divide, resulting in life-threatening cancer growth and progression. Published studies demonstrate that PAX3:FOXO1 is necessary, but not sufficient to initiate F+RMS. On the other hand side, my own preliminary studies have revealed that high PAX3:FOXO1 expression impedes F+RMS propagation in secondary recipients. These findings highlight the importance of oncogenic events other than the fusion in a permissive cell environment during both F+RMS initiation and maintenance. By leveraging my background in skeletal muscle cell biology and mouse models of sarcoma, I have developed cell sorting and transplantation tools that open the way for a series of comprehensive studies to (i) distinguish the F+RMS-initiating potential of functionally discrete mesodermal cell populations, (ii) identify oncogenic events that cooperate with PAX3:FOXO1 in F+RMS induction and (iii) directly examine PAX3:FOXO1 impact and oncogenic environment in F+RMS tumor-propagating cells. I expect that the proposed studies will further illuminate the network of cellular and molecular events in PAX3:FOXO1+ RMS and identify valuable targets for therapy.

• DFG Programme: Research Grants