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SFB 1588:  Decoding and Targeting Mechanisms of Neuroblastoma Evolution

Subject Area Medicine
Biology
Term since 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 493872418
 
The devastating childhood tumor, neuroblastoma, represents a great challenge for the pediatric oncologist. Poor survival is mainly due to relapse resulting from therapy resistance and early metastasis. Recent studies indicate treatment failure is driven by the complex process of tumor evolution, studied mainly by genetic approaches to date. Newest molecular insights obtained by CRC partners and others challenge that sequential genetic evolution is the paramount cause of relapse, and propose an additional range of non-genetic mechanisms and adaptive phenotypes behind therapy evasion. With this new view, neuroblastoma research challenges several classical cancer concepts and offers a unique and timely opportunity to study and target evolution in a tumor model with intriguing biological features having important implications for future therapy selection, monitoring and clinical trial design. The overarching 12-year aim driving this cross-disciplinary CRC is to deliver novel, improved individualized treatment strategies based on a mechanistic understanding of neuroblastoma evolution. We postulate that intense interplay occurs in neuroblastoma evolution between (i) genetic and non-genetic evolutionary mechanisms and (ii) genomic and phenotypic intratumor heterogeneity. The central CRC idea is that this interplay drives neuroblastoma cells to evade therapy. An integrated research approach is required to decode (mainly 1st and 2nd funding phases) and therapeutically target (mainly 3rd funding phase) these complex processes. Innovative technologies allow the study of tumor evolution at previously unprecedented single-cell resolution, most promising to generate new clinically relevant insights. The CRC aims to take a leading role in the emerging field of neuroblastoma evolution by (i) comprehensively characterizing, functionally evaluating and understanding its tumor intrinsic mechanisms (Research Area A); (ii) dissecting/targeting signaling driven by the neuroblastoma oncogenes MYCN and ALK (Research Area B) and (iii) illuminating how tumor cell interactions with their micro- and macroenvironments contribute to evolution (Research Area C). We will use modern data science approaches to conduct cross-platform analysis of molecular patient datasets and cross-species analyses from human, mouse, zebrafish and chicken embryo data. Uniquely, CRC1588 will have direct access to the national neuroblastoma clinical trial and national biobank, enabling immediate transfer of new molecular knowledge into academic clinical trials. The CRC constitutes a long-term research area perfectly fitting the supportive Charité and Berlin research environments, aiming to efficiently translate systems medicine approaches for diseases with high medical need. The CRC will benefit international talent recruitment and novel interdisciplinary training formats in the highly specialized field of pediatric cancer research and support stakeholder involvement.
DFG Programme Collaborative Research Centres

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Applicant Institution shared FU Berlin and HU Berlin through:
Charité - Universitätsmedizin Berlin
 
 

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