📋 Tender Overview
Giant-Leaps During Tumorigenesis: Dissecting Saltatory Evolution In Cancer ‘In The Making’
Objective
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.
Funded Under
European Research Council (Erc)
Total Cost
€ 3 428 458,00
Eu Contribution
€ 3 428 458,00
Coordinated By
European Molecular Biology Laboratory
Germany
