In vivo targeted and deterministic single cell malignant transformation

Abstract

Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develop a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. 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/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. 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 tumor growth.