Abstract LB212: Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis

Abstract Metastasis is the endpoint of tumorigenesis and is generally diagnosed at an untreatable stage. The molecular mechanisms underlying metastasis and biomarkers for early intervention are largely unknown. Here, combining a mouse model of aggressive Kras-driven non-small-cell lung cancer with in vivo fate mapping and CRISPR activation screens, we show that transcriptional amplification of oncogenic Kras promotes orthotopic lung cancer lesions growth as well as oligoclonal and polyclonal metastasis to distal organs. Mild Kras transcriptional up-regulation by CRISPRa is sufficient to fuel competitive advantage in vitro and in vivo. Parallel CRISPR activation and transcriptome sequencing show that KrasG12D amplification cooperates with sterile inflammation to drive tumor progression and with the TGFß pathway to promote metastasis. Chromatin profiling of Kras-amplifying cells uncovers transcriptional regulators potentially collaborating with oncogenic Kras to drive lung cancer and metastasis in vivo. Transcriptional modulation of KRAS dosage in mouse cell and pharmacological inhibition in human PDXs affect cell stress and differentiation programs. These observations are corroborated by bulk and single-cell RNA-seq analysis in patients. Collectively, our data on a model oncogene advance our current understanding of how KRAS drives tumor evolution, with implications for prognosis and treatment of patients. Citation Format: Michela Serresi, Sonia Kertalli, Yuliia Dramaretska, Matthias Jürgen Schmitt, Heike Naumann, Maria Zschummel, Gaetano Gargiulo. Transcriptional dosage of oncogenic KRAS drives lung adenocarcinoma cell states, progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB212.