Abstract 98: STK11 loss in KRAS driven lung adenocarcinoma promotes cancer stemness
Authors: Kyla R. Esposito, Shannon M. Prior, Cole M. Royer, David J. Seward, Paula B. Deming, Melissa N. Scheiber
Journal: Cancer Research (2025)

Abstract Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. A significant proportion (25% to 30%) of LUAD cases are driven by mutations in the KRAS oncogene, with 10-15% of these patients harboring a loss of function (LoF) mutation in the tumor suppressor gene STK11 (serine/threonine kinase 11). Loss of STK11 function in lung cancer has been associated with an immunosuppressive environment, altered metabolism, epithelial-mesenchymal transition (EMT), and destabilization of cell polarity. Retrospective patient studies have demonstrated that concurrent oncogenic KRAS and STK11 LoF mutations are associated with metastatic disease, poorer patient survival, and inferior therapeutic response. We hypothesize that STK11 loss in KRAS-driven LUAD enriches the cancer stem cell (CSC) population, resulting in a pro-metastatic phenotype. CSCs represent a small subset of tumor cells capable of self-renewal, asymmetric division, and tumor initiation. Given their role in metastasis, chemoresistance, and disease progression, CSCs could be key contributors to the aggressiveness observed in KRAS-driven STK11 LoF LUAD. To test this hypothesis, we utilized the KRAS-driven LUAD cell line NCI-H2009 and an STK11 knockout variant (∆STK11) to assess differences in CSC properties. CD44 is a common biomarker for CSC and is involved in many aspects of cancer progression. Both parental and ∆STK11 cells grown in 2-D monolayers were found to express similar levels of CD44 of mRNA and protein, as assessed by qRT-PCR and flow cytometry. However, in 3D culture, ∆STK11 multicellular spheroids (MCTs) showed a significant increase in CD44 mRNA when compared to both monolayers and parental MCTs. We have also observed increased mRNA expression of two additional CSC markers, NANOG and OCT4, in ∆STK11 MCTs compared to parental MCTs. CD44, plays a critical role in maintaining the stem-like properties of cancer cells, however, the precise mechanisms connecting CD44 expression and STK11 remain unclear. To address this, we are investigating transcription factor pathways, including NF-kB and HIPPO, to elucidate their roles in mediating enhanced CD44 expression upon STK11 loss. To characterize the function of the CSCs in KRAS-driven STK11 LoF LUAD, we have employed an embryonic zebrafish xenograft model. This in vivo system allows for real-time visualization of tumor cell survival and dissemination, providing critical insights into the metastatic behavior of cells. In conclusion, our research highlights the role of STK11 loss in driving CSC enrichment and enhancing metastatic potential in KRAS-driven LUAD. By elucidating the underlying mechanisms, we aim to identify new therapeutic targets to improve outcomes for patients with this aggressive cancer subtype. Citation Format: Kyla R. Esposito, Shannon M. Prior, Cole M. Royer, David J. Seward, Paula B. Deming, Melissa N. Scheiber. STK11 loss in KRAS driven lung adenocarcinoma promotes cancer stemness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 98.