In vivo targeted and deterministic single cell malignant transformation

Abstract

How cancer arises from a single normal cell is still the subject of active debate, affecting intervention strategies. While many cells may harbor oncogenic mutations, only a few unpredictably end-up developing a full-blown tumour. Various theories have been proposed to explain that transition but none has been tested in vivo at the single cell level. Here using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown cancer. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the "ground state theory of cancer initiation" through "short-range dispersal" of the first malignant cells preceding tumour growth.