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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,\n                    <jats:italic toggle=\"yes\">Zbp1.<\/jats:italic>\n                    The stem cell populations evolve through distinct trajectories to respond differently to subsequent introduction of oncogenic mutations, Kras\n                    <jats:sup>G12V<\/jats:sup>\n                    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\u2013derived state producing adenocarcinomas while TP53 loss drives tumorigenesis in a basal stem cell\u2013derived 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2604393123","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:04:00Z","timestamp":1791227040000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Chronic cigarette smoke exposure induces distinct stem cell states driving genetic driver\u2013specific non\u2013small cell lung cancer subtypes"],"prefix":"10.1073","volume":"123","author":[{"given":"Na","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of 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