Epithelial and microenvironmental mosaicism under stress: a two-compartment model for lung cancer development in never-smokers

The somatic mutation theory frames cancer initiation as the consequence of accumulating driver mutations. However, the widespread presence of oncogenic mutations in normal tissues and the rarity with which these clones progress to malignancy suggest that mutation alone is insufficient. Non-small-cell lung cancer in never-smokers exemplifies this paradox, as tumors often arise in the context of low mutational burden. Here, I integrate insights from developmental mosaicism and stress biology to propose a two-compartment model of cancer development. I argue that epithelial and microenvironmental genetic mosaicism establish latent initiated fields of susceptibility, while environmental and intrinsic stressors-particularly those engaging the integrated stress response-act as selective filters that determine which clones expand, adapt, or remain latent. In this framework, cancer development reflects the convergence of permissive epithelial clones, a supportive or altered microenvironment, and sustained stress. This perspective extends classical somatic evolution and field cancerization models by emphasizing the role of stress-mediated selection across interacting tissue compartments, with implications for early detection and prevention.