2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by extensive intratumoral heterogeneity, lineage plasticity, therapeutic resistance, and rapid metastasis. Increasing evidence suggests that tobacco smoke exposure contributes not only to carcinogenesis, but also to epigenetic reprogramming and acquisition of stem-like phenotypes in respiratory epithelia. Although hookah smoking is increasingly perceived as a safer alternative to cigarettes, its molecular effects remain poorly characterized. To investigate mechanisms by which tobacco smoke promotes malignant transformation and stemness, we examined the effects of cigarette smoke condensate (CSC) and water pipe condensate (WPC) in human respiratory epithelial cells and developed a lung induced pluripotent stem cell (Lu-iPSC) model to study transition from normal stem cells to cancer stem cells in SCLC.

Exposure of normal and immortalized airway epithelial cells to CSC or WPC induced dose-dependent growth inhibition accompanied by cancer-associated alterations in global histone marks, including reduced H4K16Ac and H4K20Me3 levels. Transcriptomic analyses revealed distinct yet overlapping oncogenic gene expression signatures, including consistent upregulation of epiregulin (EREG), a critical regulator of EGFR signaling implicated in lung cancer progression and cancer stem cell maintenance. These findings demonstrated that hookah smoke induces molecular and epigenetic alterations remarkably similar to conventional cigarette smoke, suggesting that tobacco smoke exposure may create a permissive cellular state favoring acquisition of stemness and malignant transformation.

To further model these early oncogenic and stemness-associated events, Lu-iPSCs derived from normal small airway epithelial cells were chronically exposed to CSC. Gene expression profiling revealed that Lu-iPSCs closely resemble SCLC rather than NSCLC, and chronic CSC exposure further enhanced stemness-associated programs, induced epithelial-mesenchymal transition markers including ZEB1 and ZEB2, impaired endodermal differentiation, increased expression of lung cancer stem cell markers such as CD44, CD133, and CD338, and promoted resistance to cisplatin and topotecan. Integrative RNA-seq analyses identified several candidate genes potentially mediating stemness and lineage plasticity in SCLC.

Collectively, these findings demonstrate that tobacco smoke exposure drives epigenetic and transcriptional reprogramming associated with carcinogenesis, stemness acquisition, and therapeutic resistance in lung epithelial cells, while establishing the Lu-iPSC platform as a clinically relevant model to investigate early events underlying SCLC initiation and progression.