Nguyen, P.-K.; Froldi, F.; Cheng, L.

While genetic mutations can promote hyperplastic growth, they do not always result in oncogenesis characterized by uncontrolled cell proliferation. Dedifferentiation, the process by which mature cells revert to a multipotent state, holds great potential for regeneration but also poses a risk of tumorigenesis. The factors that determine these opposing outcomes, however, remain unknown. We and others have previously identified the transcription factors Nerfin-1 and Lola as inhibitors of dedifferentiation. Here, we investigate how the oncogenic potential of dedifferentiation varies across different neural lineages in the Drosophila central nervous system (CNS). We found that Nerfin-1 inactivation causes oncogenic phenotypes in the central brain (CB) and the ventral nerve cord (VNC) but not optic lobe (OL). In contrast, Lola inactivation leads to tumour overgrowth specifically in the OL. We identify Chinmo, an oncogenic temporal transcription factor, and its regulation by ecdysone signalling as key determinants of these differential responses. Together, our findings reveal a mechanism by which the regulation of temporal factors like Chinmo influences the tumorigenic outcome of dedifferentiation. This provides a fundamental framework to understand how oncogenic competence arises beyond genetic mutations.