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Dissecting the Functional and Therapeutic Impact of Somatic Copy Number Alterations (SCNAs)

Project description

Study on chromosome alterations could aid research for cancer genes

Over a century ago, Theodor Boveri made a series of significant discoveries involving chromosome alterations that are the driving forces of cancer. Researchers have recently started to recognise that the somatic copy number alternations (SCNAs) are one of the most striking characteristics of cancer genomes. SCNAs can alter the expression patterns of several hundred genes simultaneously. The EU-funded CrispSCNAs project aims to address limitations in SCNA studies by combining advanced in vivo and in vitro liver cancer modelling with innovative genomic engineering technologies called clustered regularly interspaced palindromic repeats. The project will systematically investigate for the first time the functional role of SCNAs in tumour pathobiology and help identify new therapeutic strategies specifically tailored for individual SCNAs.

Objective

In 1914 Theodor Boveri described abnormal chromosome counts in cancer cells and speculated that these alterations are the driving force of cancer. Almost 100 years later it became clear that somatic copy number alterations (SCNAs) are one of the most striking characteristics of cancer genomes. SCNAs comprise deletions and amplifications of whole chromosome arms and therefore alter the expression patterns of several hundred genes simultaneously. These alterations show defined patterns suggesting selective pressure, and thus likely contain multiple driver genes, which can shape several tumorigenic properties. Therefore, studying how these events contribute to tumor development will be fundamental to understand cancer biology and develop targeted cancer therapies. However, whereas the function of recurrently mutated driver genes can be readily assessed, studying SCNAs remains challenging so far. This project will overcome these limitations by combining our unique ability to model liver cancer in vivo and in vitro with innovative CRISPR-based genomic engineering technologies. First, we will generate large chromosomal deletions in murine livers and human-derived liver organoids by CRISPR technologies and assess their functional role in cancer development. Furthermore, synthetic lethal interactions generated by these deletions will be evaluated on their therapeutic potential. Additionally, driver genes and driver gene-combinations of amplified chromosomal regions will be investigated using a novel CRISPR/Cas9-based mouse model for endogenous gene activation and chromosome engineering. Finally, we will exploit a novel concept for targeting cancer cells with specific amplifications. Our unique approach will for the first time systematically investigate the functional role of SCNAs in tumor pathobiology, identify new therapeutic strategies specifically tailored for individual SCNAs, and will therefore have high impact for future efforts to understand and combat cancer.

Host institution

UNIVERSITATSKLINIKUM HEIDELBERG
Net EU contribution
€ 1 400 000,00
Address
IM NEUENHEIMER FELD 672
69120 Heidelberg
Germany

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Region
Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 400 000,00

Beneficiaries (2)