Anaplastic rhabdomyosarcoma in TP53 germline mutation carrier. Image taken from Hettmer et al, Cancer, 2014.
PD Dr. Simone Hettmer
Soft-tissue sarcomas are an important challenge in pediatric oncology. These tumors form a heterogeneous group of cancers of non-hematopoietic, mesodermal tissues. They are disproportionately common in children and adolescents. Most patients with high-risk metastatic disease die despite intensive therapy, and those who survive face lifelong, significant late effects of treatment.
Work in the Pediatric Sarcoma Laboratory aims at a better understanding of the cellular, molecular and metabolic underpinnings of sarcomas, which is a prerequisite for improving the diagnostic classification, risk stratification and therapy of these devastating cancers.
The basic research in the Pediatric Sarcoma Laboratory is complemented by close interaction with the Co-operative Soft Tissue Sarcoma Study Group, which is led by Simone Hettmer under the auspices of the German Society for Pediatric Oncology and Hematology.
- Christoph Bauer, PhD student (cooperation with Prof. Dr. Bernd Kammerer, Metabolomics Core Facility, ZBSA Freiburg)
- Moritz Petzold, cand. med.
- Meret Quante, cand. med.
- Carla Regina, PhD
- Michaela Schneider, MTA
- Jakob Siebert, cand. med. (cooperation with Dr. Friedrich Kapp, Department of Pediatric Hematology/ Oncology Freiburg)
- Julia Würtemberger, MD
- Sina Angenendt
- Oliver Uckunkaya
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. (Dr. Carla Regina, post-doctoral researcher)
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. (Christoph Bauer, PhD student & Meret Quante, 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. (Ph.D. student to be determined)
DICER1 in pediatric rhabdomyosarcoma
DICER1 tumor predisposition has been linked to RMS of the gynecological tract. These tumors are thought to take a favorable course, but data on clinical manifestation and specific therapeutic requirements are scarce. We are investigating the clinical characteristics and presence of DICER1 hotspot mutations in tumor tissue in children with urogenital RMS registered by the Cooperative Weichteilsarkom (CWS) study group. (Moritz Petzold, cand. med.)
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/
- S Hettmer*, NM Archer, GR Somers, A Novokmet, AJ Wagers, L Diller, C Rodriguez-Galindo, LA Teot, D Malkin. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014 Apr 1;120(7):1068-75 (* corresponding author).
- K Kikuchi, S Hettmer, MI Aslam, JE Michalek, W Laub, BP Rubin, AJ Wagers, C Keller. The Pax3:Foxo1a Translocation Product is a Dynamically-Expressed Modifier of the Alveolar Rhabdomyosarcoma Tumor Phenotype. PLOS Genetics. 2014;10(1):e1004107.
- A Castiglioni* and S Hettmer*, MD Lynes, TN Rao, D Tchessaolova, I Sinha, BT Lee, YH Tseng, AJ Wagers. Isolation of progenitors that exhibit myogenic/osteogenic bipotency in vitro by fluorescence activated cell sorting from human fetal muscle. Stem Cell Reports. 2014;2(1):92-106 (* shared first authorship).
- 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. The Hippo Transducer YAP1 Transforms Activated Satellite Cells and is a Potent Effector of Embryonal Rhabdomyosarcoma Formation. Cancer Cell. 2014 Aug 11;26(2):273-87.
- S Hettmer, AC Schinzel, D Tchessalova, M Schneider, CL Parker, R Bronson, NG Richards, W Hahn, AJ Wagers. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. Epub Elife. 2015 Oct 24;4.
- 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. Clinical and mutational spectrum of highly differentiated, PAX:FOXO1 fusion-negative rhabdomyosarcoma. Cancer. 2018 Feb 20.
- Prof. Dr. Bernd Kammerer, Center for Biological Systems Analysis Medical Center- University of Freiburg
- Prof. Dr. Beat Schäfer, KISPI, Experimentelle Infektiologie und Krebsforschung, Universität Zürich
- Prof. Dr. Dr. Melanie Börries, Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg
- Dr. Manching Ku, Pediatric Hematology and Oncology, Medical Center, University of Freiburg
- Prof. Dr. Olaf Groß, Institute of Neuropathology, Medical Center, University of Freiburg
- CWS Studiengruppe, Olgahospital Stuttgart