In vivo multiplexed screen reveals a critical role of Keap1/Nrf2 pathway in small cell lung cancer [RNAseq]

Approximately 15% of all lung cancer cases are small cell lung cancer (SCLC), which originates from neuroendocrine cells lining the airways (bronchi) of the lung. SCLC is known for its aggressive nature and swift growth, resulting in a five-year survival rate of around 6%. Understanding the genetic pathways that drive tumor development remains an ongoing challenge. In our study, we employed an in vivo multiplexed approach, known as Tuba-seq, to investigate the impact of the functional loss of 18 putative tumor suppressors. Our screening unveiled Pten and Keap1 as top candidates; knocking out either one promoted both tumor initiation and progression. We identified the Keap1/Cul3/Nrf2 pathway as a pivotal regulator for SCLC development, particularly in regulating the susceptibility of SCLC to ferroptosis. Our work not only established an in vivo multiplexed approach for assessing the role of tumor suppressors in SCLC but also uncovers a previously unappreciated role of Keap1 in SCLC. Tuba-seq approach was utilized to profile effects of inactivating 18 putative tumor suppressors in SCLC. Keap1 was identified as a robust tumor suppressor in this study, with its inactivation promoting tumor iniation and progression in SCLC. To investigate how Keap1 regulates SCLC development transcriptomes were profiled in control and Keap1 depleted QKO tumors (about 4 months after virus injection) by mRNA-seq (paired-end, 3 control samples and 3 Keap1 knockout samples).