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433 Projects, page 1 of 87
  • Funder: European Commission Project Code: 101098056
    Overall Budget: 3,428,460 EURFunder Contribution: 3,428,460 EUR

    Tumorigenesis is an evolutionary process driven by gradual mutation acquisition to confer selective advantages to somatic cells. DNA rearrangements are the most common cancer driver mutation, outnumbering base substitutions. Rearrangements amplify, disrupt and fuse genes or alter their gene regulation, ultimately driving adaptive changes to initiate cancer, metastasis and therapy resistance. Cancer genomics has revealed that most of these alterations arise as complex genomic rearrangements (CGRs), where a multitude of changes arise in a short time. While in most cases deleterious to the cell, in rare cases CGRs confer an adaptive malignant phenotype in one giant-leap through saltatory evolution events (SEEs) – reminiscent of the “hopeful monsters” theorised by Goldschmidt. Given their potential to overcome strong selective barriers, it has been proposed that SEEs draw the line between benign lesions and lethal cancer, and understanding their mechanisms is thus fundamental to tumour biology. However, the identity of cells undergoing SEEs has remained elusive, with cancer genomics studies focusing typically on long-established cancers rather than early or even initiating cancer cells. Intriguingly, CGRs are largely explained by cascades of atypical cell nuclei (i.e., nuclear atypias) fueling rearrangement formation, providing an opportunity to study SEEs. Building a novel automated AI-driven framework that couples imaging and single-cell multi-omics, we will leverage nuclear atypias as a phenotypic indicator to dissect principles and mechanisms of SEEs ‘in the making’, and advance fundamental cancer biology. Using highly controllable cell lines and organoid models of colorectal cancer (CrC), a tumour thought to be driven by SEEs, we will unravel pathways, genetic contexts and chromosome-level constraints determining SEEs. Finally, via validation in patient samples we will pave the way to determining SEEs in future clinical studies to advance precision oncology.

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  • Funder: European Commission Project Code: 101031265
    Overall Budget: 176,036 EURFunder Contribution: 176,036 EUR

    The sarcomeric protein titin (TTN) is mutated in 30% of patients with familial dilated cardiomyopathy (DCM), a common heart disease that is a global threat to the aging society. Aberrant alternative splicing of TTN is causally linked to DCM, therefore, to understand mechanisms of TTN splicing is crucial for developing therapeutic options, which so far do not exist for DCM. RBM20, a protein that regulates alternative splicing of TTN, is also mutated in many patients with an aggressive form of DCM. How RBM20 mediates alternative splicing of TTN is largely unknown. Due to its gigantic size, TTN mRNA is often precluded from transcriptome-wide single-cell analysis. Here, I aim to understand alternative splicing of TTN mediated by RBM20 on a single-cell level. To this end, I propose to develop a method for the detection of all transcript isoforms that can be produced by the 364 exons of TTN. Using this tool, termed TITIN-seq, together with complementary stem cell-based assays, I seek to analyze changes in the repertoire of TTN isoforms upon disease-relevant mutations in the RBM20 gene. Moreover, TITIN-seq is used to identify novel splice regulators of TTN, which, together with RBM20, could complete the picture of alternative splicing of TTN. The overarching goal is to construct a comprehensive map of TTN splicing by integrating data of all its isoforms in single cells and its regulatory proteins. I envision that knowledge of such a splice map can be exploited for developing therapeutic strategies to revert aberrant splicing of TTN in patients with DCM.

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  • Funder: European Commission Project Code: 236515
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  • Funder: European Commission Project Code: 219834
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  • Funder: European Commission Project Code: 330111
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