Current research in our group includes the following projects:
Plasticity of PAX3:FOXO1 fusion-positive RMS
PAX3:FOXO1 expression in alveolar RMS fluctuates at the single cell level. Our ongoing work aims at demonstrating that PAX3:FOXO1 expression levels correlate with key determinants of malignant behavior and susceptibility to compounds with anti-sarcoma activity.
Asparagine dependence of sarcomas
Sarcoma growth depends on sufficient availability of the non-essential amino acid asparagine. Asparaginase reduces asparagine availability and sarcoma growth. The compensatory mechanisms, utilized by sarcoma cells to counteract the effects of asparagine deprivation, may serve as targets for combination therapies. To modulate asparagine availability in sarcoma cells, we are using lentivirally delivered shRNAs to knock down asparagine synthetase, and we are exposing cells to different concentrations of asparagine. Global metabolomics changes are being evaluated by mass spectrometry to identify actionable adaptive mechanisms. (Moritz Petzold, cand. med.)
Recent evidence supports that 12-19% of all sarcomas arise in the context of monogenic, cancer-predisposing germline lesions. We are working on risk assessment tools to identify children with sarcoma-predisposing germline conditions based on full consideration of cancer history, sarcoma manifestation and sarcoma genotype. (Julia Würtemberger, MD & Manching Ku, PhD)
TP53 in RMS
We are investigating the impact of aberrant TP53, introduced at different time points during tumor evolution, on rhabdomyosarcoma phenotype, target expression and treatment susceptibility. (Ebrahem Hamed, PhD student)
For information about our pediatric sarcoma/sarcoma predisposition clinic, please visit the Sarcoma Clinic pages on the website of the Freiburg Center for Pediatrics and Adolescent Medicine.
Complete list of published works by Simone Hettmer: https://www.ncbi.nlm.nih.gov/myncbi/101blyh9NiOAL/bibliography/public/
- Patterns of Prior and Subsequent Neoplasms in Children and Adolescents With Soft Tissue Sarcomas. Uckunkaya O, Nöllke P, Hallmen E, Becker C, Stegmaier S, Sparber-Sauer M, Vokuhl C, Koscielniak E, Hettmer S. J Pediatr Hematol Oncol. 2020 Jul;42(5):e265-e270. doi:10.1097/MPH.0000000000001837
- Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma. Mohamed AD, Shah N, Hettmer S, Vargesson N, Wackerhage H. Sci Rep. 2018;8(1):15674. Published 2018 Oct 23. doi:10.1038/s41598-018-33852-7
- Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. S Hettmer*, NM Archer, GR Somers, A Novokmet, AJ Wagers, L Diller, C Rodriguez-Galindo, LA Teot, D Malkin. Cancer. 2014 Apr 1;120(7):1068-75 (* corresponding author). doi:10.1002/cncr.28507.
- Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma. K Kikuchi, S Hettmer, MI Aslam, JE Michalek, W Laub, BP Rubin, AJ Wagers, C Keller. PLOS Genetics. 2014;10(1):e1004107. doi:10.1371/journal.pgen.1004107
- Isolation of progenitors that exhibit myogenic/osteogenic bipotency in vitro by fluorescence activated cell sorting from human fetal muscle. A Castiglioni* and S Hettmer*, MD Lynes, TN Rao, D Tchessaolova, I Sinha, BT Lee, YH Tseng, AJ Wagers. Stem Cell Reports. 2014;2(1):92-106 (* shared first authorship). doi:10.1016/j.stemcr.2013.12.006
- The Hippo Transducer YAP1 Transforms Activated Satellite Cells and is a Potent Effector of Embryonal Rhabdomyosarcoma Formation. AM Tremblay, E Missiaglia, GG Galli, S Hettmer, R Urcia, M Carrara, RN Judson, K Thway, G Nadal, JL Selfe, G Murray, RA Calogero, C De Bari, PS Zammit, M Delorenzi, AJ Wagers, J Shipley, H Wackerhage and FD Camargo. Cancer Cell. 2014 Aug 11;26(2):273-87. doi:10.1016/j.ccr.2014.05.029
- Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. S Hettmer, AC Schinzel, D Tchessalova, M Schneider, CL Parker, R Bronson, NG Richards, W Hahn, AJ Wagers. Elife. 2015 Oct 24;4. doi:10.7554/eLife.09436
- Clinical and mutational spectrum of highly differentiated, PAX:FOXO1 fusion-negative rhabdomyosarcoma. L Teot, M Schneider, AR Thorner, J Tian, Y Chin, M Ducar, L Lin, M Wlodarski, HE Grier, CMD Fletcher, P van Hummelen, SX Skapek, DS Hawkins, AJ Wagers, C Rodriguez-Galindo, S Hettmer. Cancer. 2018 Feb 20. doi:10.1002/cncr.31286