Molecular mechanisms of copy-neutral loss of heterozygosity

Cancer is one of the deadliest human diseases; a continuously increasing threat to human health. Understanding the mechanisms that lead to malignancy is central to the development of therapeutic strategies. The alternation of one of the two copies of a gene that suppresses tumor formation is often followed with by additional events leading to the loss and replacement of the remaining healthy copy by a replicate of the mutated one. This is a common occurrence in human malignancies and leads to the complete inactivation of the affected gene. Such events are called copy-neutral loss of heterozygosity or in short cnLOH. Despite the frequency and relevance of cnLOH events, no mechanism has been discovered to-date. To understand more about these events we will use a groundbreaking 3D system, developed in our lab, which models human-specific aspects of brain development, called cerebral organoids. We will track these events in different organoid model which recreate brain tumor formation caused by alterations in different genes where the emerging tumors are known to undergo cnLOH events. The simplicity of this system will allow us to detect such events in very high throughput and help determine where and when they occur during tumorigenesis in cerebral organoids. We will perform genetic screens to uncover the mechanism(s) that controls cnLOH events and test their relevance during tumorigenesis in cerebral organoids. By comparing data from these screens we will assess whether the same or distinct mechanisms lead to cnLOH. Applying a wide panel of approaches has the potential to finally uncover the mechanisms governing cnLOH events during tumorigenesis and could give rise to unique new therapeutic strategies in the treatment of relevant pathologies and cancer in general.

No additional funding sources recorded.