Translational Pediatric Sarcoma Research

Tumorigenesis in the context of molecular signaling pathways of child development

Certain oncogenes often hijack or interfere with molecular signaling pathways important for child development, thereby conferring a considerable growth advantage to tumor cells. We explore the mechanisms through which oncogenes arrest sarcoma cells in a specific 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. Chemotherapy-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 ‘cell stress’ on the clonal and sub-clonal level. Therefore, we strive for illuminating the (epi)genetic basics and biological mechanisms of tumor-heterogeneity in order to identify new biomarkers for individualized risk-stratification. By means of these biomarkers we can predict the response to certain treatments and better assess which targeted therapeutics may help to overcome resistance to conventional (chemo)therapeutics.

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

The team Translational Genomics (Prof. T. Grünewald) systematically establishes multi-dimensional omics-datasets of a large number of pediatric sarcomas and correlates molecular alterations with clinical data to identify new driver mutations, disease-relevant drug targets and prognostic/predictive biomarkers, and to create resources for hypothesis generation and functional validation for future projects.

The team Mechanisms of Cancer Progression (Dr. F. Cidre-Aranaz) aims at deconvoluting the multilayered process underlying cancer progression and metastasis. For this purpose, systems biology approaches based on multi-omics data and clinical information with functional in vitro and in vivo experiments will be combined to identify treatable vulnerabilities in pediatric sarcomas that can prevent metastasis.

The team Innovative Therapies (Dr. S. Ohmura) is investigating potential therapeutic targets for pediatric sarcomas in preclinical models. The focus here lies in developing and testing new targeted therapy approaches that enable more effective therapy with fewer side effects, especially for patients with chemo resistant tumors.