Abstract
Cigarette smoke-induced chronic inflammation (CI) potentiates development of non–small cell lung cancer (NSCLC) by mediating genetic and epigenetic events. Using normal lung organoids (LOs), we define how chronic cigarette smoke condensate (CSC) exposure drives two separate stem cell populations to evolve premalignant states harboring progressive epigenetic and linked transcriptomic abnormalities in the absence of major driver mutations. These dynamics facilitate evolution of an immune evasive state with downregulation of inflammatory pathways and accompanying death signals mediated by epigenetic silencing of PANoptosis regulator,
Zbp1.
The stem cell populations evolve through distinct trajectories to respond differently to subsequent introduction of oncogenic mutations, Kras
G12V
and loss of Tp53, to induce one step transformation of CSC exposed organoids resulting in two major NSCLC subtypes. Kras mutations drive tumorigenesis primarily in a bronchioalveolar stem cell–derived state producing adenocarcinomas while TP53 loss drives tumorigenesis in a basal stem cell–derived state resulting in squamous cell carcinomas. CSC-induced downregulation of Zbp1 and interferon signaling is further potentiated in tumors with mutation-specific changes marked by decreased expression in Kras-mutant contexts. Our findings define unique transcriptomic profiles in CI-induced stem cell states and reveal a key role for cell death pathway-associated genes in potentiating oncogenic drivers to promote NSCLC. Together, our data suggest strategies to predict cancer risk and enable early interception.