Zelluläre und molekulare Voraussetzungen der Initiierung und Erhaltung PAX3:FOXO1-positiver Rhabdomyosarkomen

• Antragstellerin: Professorin Dr. Simone Hettmer
• Fachliche Zuordnung: Kinder- und Jugendmedizin ; Hämatologie, Onkologie ; Zellbiologie
• Förderung: Förderung von 2016 bis 2020
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 290640517

• Erstellungsjahr: 2021

Zusammenfassung der Projektergebnisse

Rhabdomyosarcoma (RMS), the most common cancer of the soft tissues in children and adolescents, comprises two main genotypes defined by the presence or absence of rearrangements of the PAX gene rearrangements, which act as major oncogenic drivers. PAX3:FOXO1 (P3F) has been detected in 55% and PAX7:FOXO1 (P7F) in 22% of alveolar histology RMS tumors. Patients with RMS harboring P3F rearrangements are more likely to be metastatic at presentation and relapse quickly despite highly aggressive therapy. Extremely poor survival rates call for a deeper understanding of the biology of P3F+ RMS. We show that low-passage mouse Myf6Cre,Pax3:Fkhr,p53 RMS cell lines and low-passage human RMS cell cultures contain cells expressing markedly heterogenous P3F levels. At the single cell level, P3F levels fluctuate over time. P3Fhigh cells are mostly in the G2/ M phase of the cell cycle, and higher P3F expression correlates with higher proliferation rates. By contrast, P3Flow U23674 cells are mostly in the G0/ G1 phase of the cell cycle and reorganize their cytoarchitecture to produce a cellular phenotype prone to adhesion and migration. These differences translate into higher clonal activity and tumor-propagating capacity of P3Flow U23674 cells. Because of its central role in RMS malignancy, the P3F fusion oncogene has generally been considered an ideal target to selectively attack tumor cells. Yet, our data clearly indicate that curing P3F-rearranged RMS may go far beyond eliminating all P3Fhigh cell states at any given point in time. Rather, findings from our experiments indicate that, as P3F-rearranged RMS cells transition between P3Flow and P3Fhigh states, they adopt and shed profoundly different features of malignant behavior. Cell-to-cell variability in P3F expression and adaptive plasticity may provide a critical advantage during tumor progression. Future experiments are needed to obtain a deeper understanding of fluctuations in P3F expression at the cellular level in RMS.

Projektbezogene Publikationen (Auswahl)

• Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma. Sci Rep. 2018, 8(1):15674
  AD Mohamed, N Shah, S Hettmer, N Vargesson, H Wackerhage
  
• Clinical and mutational spectrum of highly differentiated, PAX:FOXO1 fusionnegative rhabdomyosarcoma. Cancer. 2018; 124(9):1973-1981
  LA Teot, M Schneider, AR Thorner, J Tian, Y Chi, M Ducar, L Lin, M Wlodarski, HE Grier, CDM Fletcher, P van Hummelen, SX Skapek, DS Hawkins, AJ Wagers, C Rodriguez-Galindo, S Hettmer
  
• The landcsape of genomic alterations across childhood cancer. Nature. 2018, 555(7696):321-327
  SN Gröbner, BC Worst, J Weischenfeldt, ..., S Hettmer, ..., SM Pfister
  
• Insights into pediatric rhabdomyosarcoma research: Challenges and goals. Pediatr Blood Cancer. 2019 Oct;66(10):e27869
  ME Yohe, CM Heske, E Stewart, PC Adamson, N Ahmed, CR Antonescu, E Chen, N Collins, A Ehrlich, RL Galindo, BE Gryder, H Hahn, S Hammond, ME Hatley, DS Hawkins, MN Hayes, A Hayes- Jordan, LJ Helman, S Hettmer, MS Ignatius, C Keller, J Khan, DG Kirsch, CM Linardic, PJ Lupo, R Rota, JF Shern, J Shipley J, S Sindiri, SJ Tapscott, CR Vakoc, LH Wexler, DM Langenau
  
• Myxoid liposarcoma: it's a hippo's world. EMBO Mol Med. 2019 May;11(5)
  C Regina and S Hettmer
  
• Growth inhibition associated with disruption of the actin cytoskeleton by latrunculin A in rhabdomyosarcoma cells. PLOS One. 2020, 5(9):e0238572
  J Würtemberger, D Tchessalova, C Regina, C Bauer, M Schneider, AJ Wagers, S Hettmer
  
• Lack of electron acceptors contributes to reductive stress and growth arrest in asparagine-starved sarcoma cells. Cancers (Basel). 2021, 13(5):1151
  C Bauer, M Quante, C Regina, M Schneider, G Andrieux, O Gorka, O Gross, M Boerries, B Kammerer, S Hettmer
  
• Negative correlation of single-cell PAX3:FOXO1 expression with tumorigenicity in rhabdomyosarcoma. Life Sci Alliance. 2021 Jun 29;4(9):e202001002
  C Regina, E Hamed, G Andrieux, S Angenendt, M Schneider, M Ku, M Follo, M Wachtel, E Ke, K Kikuchi, AG Henssen, BW Schäfer, M Boerries, AJ Wagers, C Keller, S Hettmer
  
• Pathology of childhood rhabdomyosarcoma: A consensus opinion document from the Children's Oncology Group, European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. Pediatr Blood Cancer. 2021, 68(3):e28798
  ER Rudzinski, A Kelsey, C Vokuhl, CM Linardic, J Shipley, S Hettmer, E Koscielniak, DS Hawkins, G Bisogno