Abstract
Cancer cells keep accumulating alterations leading to a diversification through space and time. This diversity in the composition of cancer cells represents a major challenge for cancer treatment as it is difficult (if possible, at all) to find a treatment that works on all the cancer cells. The clonal evolution model introduces evolutionary tools in oncology to make sense of this evolution of the cancer cells. In this model cancer cells are regrouped in clones—populations of cells that share a common identity (traditionally a common set of driver mutations) inherited from a common ancestor cell. This allows us to reconstruct the evolutionary history of the tumour (and metastases), and to track its evolution through time. This has, for example, allowed researchers to identify mutations involved in resistance to targeted therapies (e.g., EGFRT790M induces resistance to first generation EGFR inhibitors). But reconstruction of the clonal evolution is far from an easy task, both pragmatically and conceptually. The conceptual issue can be easily grasped by just indicating that the two main characteristics of clones —genealogy and identity— pull in opposite directions. Genealogically speaking, all cancer cells have a common ancestor, the first transformed cell, so each cancer is one big clone. But cancer cells of a given cancer are all unique. Thus, regrouping cancer cells into clones requires making a choice with regards to which criterion to use. Traditionally, the choice is to regroup cells according to their driver mutations, as these are conceived as the only mutations that impact cells’ properties, and they are easily tractable including in clinics. We take issue with this choice. In this talk, we will first deconstruct the notion of clone in oncology, highlighting that it relies on the following dubious assumptions: (1) driver mutations can be distinguished from passengers; (2) driver mutations provide a good proxy of cancer cell phenotype; (3) intraclonal heterogeneity can be ignored. This will lead us to argue that the notion of clone must be revised. Second, we will argue in favour of a change in the understanding of clonal identity. Our suggestion is to regroup cells according to their similarities, distinguishing clonal (lineage-dependent) similarities, from non-clonal (lineage-independent) similarities (e.g., similarities that are stochastic or induced by phenotypic plasticity). Both types of similarities can contribute to explaining cancer cells properties, such as response to treatment. But only the former can contribute to clonal evolution as whatever causes the similarity is inherited by descendant cells of that lineage. Third, we will explore the benefit of this conceptual turn. It opens new research programs on how to analyse the evolutionary dynamics in cancer cells, experimentally and computationally. We will show the first results of an original experimental set-up we have developed to focus on the inheritance of functional properties, with no prior assumption regarding what exactly causes the observed lineage-dependent similarities.
