Translational Pediatric Sarcoma Research

Division of Translational Pediatric Sarcoma Research

Prof. Dr. Dr. Thomas Grünewald

Translational spectrum of methods: histology, omics-analyses, preclinical models, correlation with clinical data
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The mission of the division of Translational Pediatric Sarcomas Research, which corresponds to the KiTZ division of the same name, is to improve treatment options for children and adolescents affected by sarcomas. We aim at uncovering disease mechanisms that can be used diagnostically and therapeutically to improve the long-term chances of recovery of our young patients. The focus lies on new methods that are essential for correct diagnosis and the choice of the best possible therapy. We also investigate less aggressive therapies and new approaches to overcome drug resistance of tumors. In this regard, one special objective is to decipher the interactions between acquired mutations and innate natural variants of the genome, which can play a decisive role in the development and progression of cancer, particularly in Ewing sarcoma.

We aim at developing novel therapeutic strategies based on new insights into the molecular mechanisms of disease following two major lines of research (see research areas). Our investigations start with the analysis of the patients’ tumors in situ, followed by studying patient-derived cell lines using a wide variety of in silico, in vitro, and in vivo techniques.

The division is supported by the Barbara und Wilfried Mohr Stiftung.

Research areas

Tumorigenesis in the context of developmental pathways
Dominant oncogenes often hijack or interfere with developmental pathways thereby conferring a considerable growth advantage to tumor cells. We are interested in the mechanisms through which oncogenes arrest sarcoma cells in a lineage-specific, early-committed but yet largely undifferentiated state via deregulation of key developmental pathways, and how they cooperate with them to promote tumorigenesis and cancer progression.

Therapy resistance, tumor heterogeneity, and predictive biomarkers
Primary and/or secondary resistance to conventional chemotherapeutic drugs is a frequent event in pediatric sarcoma. Chemo-resistance is a highly specific process in which tumors become resistant to certain drugs while maintaining (limited) susceptibility toward others. Underlying to this resistance is considerable plasticity due to intra-tumor heterogeneity, which enables the adaptation to therapeutic stress on the clonal and sub-clonal level. We strive for illuminating the genetic basis and biological mechanisms of tumor-heterogeneity and aim at identifying novel biomarkers for individualized risk-stratification, prediction of treatment response, and to indicate which targeted therapeutics may help overcoming resistance to conventional (chemo)therapeutics.

The above-mentioned research areas are addressed by three highly synergistic teams within the division of Translational Pediatric Sarcoma Research:

The team Translational Genomics (T. Grünewald) systematically established multi-dimensional omics-datasets of a large number of pediatric sarcomas and correlates identified molecular alterations with clinical data to identify novel driver mutations, druggable targets and prognostic/predictive biomarkers, and to create resources for hypothesis generation and functional validation.

The team Mechanisms of Cancer Progression (F. Cidre-Aranaz) aims at deconvoluting the multilayered process underlying cancer progression and metastasis. We employ systems biology approaches combining in vitro and in vivo functional characterization of potential targets with multi-omics data and clinical information to identify targetable vulnerabilities in pediatric sarcomas.

The team Innovative Therapies (S. Ohmura) investigates potential therapeutic targets for pediatric sarcomas through comprehensive analyses crossing omics and clinical data sets. Our scope lies in developing targeted approaches with a particular emphasis on therapy-refractory tumors, which may enable more effective therapies with less adverse effects.

Contact

Prof. Dr. Dr. Thomas Grünewald
Translational Pediatric Sarcoma Research (B410)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3718

Selected Publications

  • Li J, Ohmura S, Marchetto A, Orth MF, Imle R, Dallmayer M, Musa J, Knott MML, Hölting TLB, Stein S, Funk CM, Sastre A, Alonso J, Bestvater F, Kasan M, Romero-Pérez L, Hartmann W, Ranft A, Banito A, Dirksen U, Kirchner T, Cidre-Aranaz F, Grünewald TGP. Therapeutic targeting of the PLK1-PRC1-axis triggers cell death in genomically silent childhood cancer. Nat Commun 2021 Sept;12(1):5356
  • Marchetto A, Ohmura S, Orth MF, Knott MML, Colombo MV, Arrigoni C, Bardinet V, Saucier D, Wehweck FS, Li J, Stein S, Gerke JS, Baldauf MC, Musa J, Dallmayer M, Romero-Pérez L, Hölting TLB, Amatruda JF, Cossarizza A, Henssen AG, Kircher T,Moretti M, Cidre-Aranaz F, Sannino G, Grünewald TGP. Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma. Nat Commun 2020 May;11(1):2423
  • Musa J, Cidre-Aranaz F, Aynaud MM, Orth MF, Knott MML, Mirabeau M, Mazor G, Varon M, Hölting TLB, Grossetête S, Gartlgruber M, Surdez D, Gerke JS, Ohmura S, Marchetto A, Dallmayer M, Baldauf MC, Stein S, Sannino G, Li J, Romero-Pérez L, Westermann F, Hartmann W, Dirksen U, Gymrek M, Anderson ND, Shlien A, Rotblat B, Kirchner T, Delattre O, Grünewald TG. Cooperation of cancer drivers with germline regulatory variants shapes clinical outcomes. Nat Commun 2019 Sept;10(1):4128
  • Grünewald TG*, Cidre-Aranaz F*, Surdez D, Tomazou EM, de Alava E, Kovar H, Sorensen PH, Delattre O, Dirksen U. Ewing sarcoma. Nat Rev Dis Primers 2018 Jul;4(1):5
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