Abstract

Glioblastoma is the most aggressive primary brain tumour in adults and, despite surgery, radiotherapy and chemotherapy, it inevitably tends to recur. One of the reasons for its resistance is its ability to evolve: within the same tumour, different cell populations, or clones, coexist, emerging and changing over time. Treatments may eliminate some populations, but indirectly favour the survival and expansion of other, more resistant ones.

The DeCoD project stems from our discovery of massive clonal extinction during the early stages of glioblastoma evolution: the majority of the initial clones disappear, whilst a few acquire a competitive advantage and become predominant. This selection does not appear to depend solely on genetic mutations: random and reversible variations in gene expression can alter, even if only temporarily, the cells’ ability to grow and survive.

DeCoD will investigate how this diversity arises and which signals determine the emergence and fate of ‘winning’ and ‘losing’ clones. Mouse models and patient-derived cells will be analysed in detail using genetic barcoding, which allows the lineage of individual cells to be traced over time, integrated with single-cell transcriptomics, spatial transcriptomics and chromatin accessibility analysis. In this way, we will be able to determine which molecular factors underlie fitness diversity and verify the existence of mechanisms of direct competition between tumour cells. CRISPR screening and pharmacological tests will then enable us to verify the role of the identified mechanisms and to measure the sensitivity of the different clones to drugs.

The ultimate aim is to transform clonal competition from a driver of tumour evolution into a therapeutic vulnerability: to intervene in the rules of competition to hinder the most aggressive clones, steer the tumour towards more treatable states, and design combinations or sequences of drugs capable of pre-empting its adaptation.