Cancer was long considered a primarily genetic disease driven by the sequential accumulation of DNA mutations. For many years, the clonal evolution model predominated, giving the idea that tumours arise from a single mutated cell that expands into a uniform population. That is, cancer was thought to be a fairly homogeneous entity, in which tumour cells share the same genetic and functional characteristics. However, although foundational, this model overlooked the dynamic interplay between the evolving cancer genome and the selective pressures of its microenvironment. This dynamic interaction profoundly affects the behaviour of transformed cells, leading to diverse fitness advantages of individual cells within a tumour and, thus, remarkable intratumoural heterogeneity.

In 2012, Gerlinger et al. challenged the prevailing view of linear tumour progression, revealing the complex and branched evolution of cancer. This pivotal work reshaped our understanding of cancer biology, demonstrating that tumours are heterogeneous ecosystems of evolving cell populations. At the time, differences in morphology, gene expression and drug response within tumours had been observed, hinting at a more profound complexity. However, although it was recognized that tumours were not uniform masses of cells, the true extent and implications of this heterogeneity remained largely unexplored.