The rise of RAS: how gradual oncogene activation shapes the OIS spectrum

Abstract

Excessive levels of oncogenic RAS expression in normal cells trigger reactive cellular senescence, known as oncogene-induced senescence (OIS)—a putative autonomous tumor-suppressive mechanism. However, the monoallelic expression of oncogenic RAS from the endogenous locus often fails to induce senescence, at least in the short term. Consequently, whether robust senescence characterizes the preneoplasia driven by oncogenic RAS under physiological conditions has been debated. A key challenge is the highly heterogeneous nature of senescence at both the population and single-cell levels. Notably, increasing evidence suggests that RAS levels are gradually upregulated during the development of tumors driven by oncogenic RAS. To address the complex relationship between diverse oncogenic responses, including senescence and tumor initiation, we introduce the concept of an OIS spectrum, where oncogenic dosage-dependent cellular states lie between normal cells and full senescence. Intermediate “sub-OIS” states may play a critical role in tumor initiation, potentially providing one explanation for the ongoing debate.