Deciphering cancer cell state plasticity with single-cell genomics and artificial intelligence

Cancer stem cell plasticity refers to the ability of tumour cells to dynamically switch between states—for example, from cancer stem cells to non-cancer stem cell states. Governed by regulatory processes, cells transition through a continuum, with this transition space often referred to as a cell state landscape. Plasticity in cancer cell states leads to divergent biological behaviours, with certain cell states, or state transitions, responsible for tumour progression and therapeutic response. The advent of single-cell assays means these features can now be measured for individual cancer cells and at scale. However, the high dimensionality of this data, complex relationships between genomic features, and a lack of precise knowledge of the genomic profiles defining cancer cell states have opened the door for artificial intelligence methods for depicting cancer cell state landscapes. The contribution of cell state plasticity to cancer phenotypes such as treatment resistance, metastasis, and dormancy has been masked by analysis of ‘bulk’ genomic data—constituted of the average signal from millions of cells. Single-cell technologies solve this problem by producing a high-dimensional cellular landscape of the tumour ecosystem, quantifying the genomic profiles of individual cells, and creating a more detailed model to investigate cancer plasticity (Genome Res 31:1719, 2021; Semin Cancer Biol 53: 48-58, 2018; Signal Transduct Target Ther 5:1-36, 2020). In conjunction, rapid development in artificial intelligence methods has led to numerous tools that can be employed to study cancer cell plasticity.