Abstract Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality, with the KRAS/STK11 (LKB1) co-mutant subtype displaying marked therapeutic resistance and metastatic potential. Metastatic success depends on the ability of circulating tumor cells (CTCs) to withstand the oxidative and mechanical challenges of blood flow, yet the contribution of STK11 loss to fluid shear stress (FSS) tolerance is not fully defined. Using our embryonic zebrafish xenograft model with KRAS-mutant parental and STK11-null LUAD lines, we conducted longitudinal imaging of CTC behavior in physiologic circulation. Under glutamine-deprived conditions that simulate metabolic stress, STK11-null cells exhibited higher micrometastatic burden and increased frequency of extravasation at four days post-injection compared with parental controls. RNA-seq performed under glutamine deprivation and analyzed using Reactome GSEA revealed enrichment of broad stress- and stimulus-response pathways. An FSS-specific gene panel further demonstrated enrichment of shear-adaptive programs, notably NRF2-mediated antioxidant responses, highlighting the need to define these programs directly in vivo. Our data support a model in which STK11 loss facilitates CTC persistence and outgrowth through NRF2-driven survival mechanisms engaged under oxidative and mechanical strain. Ongoing studies leverage high-speed confocal imaging (200–500 fps) and Fiji/ImageJ velocity quantification to map the relationship between shear forces and CTC survival, with planned pharmacologic tuning of cardiac output to modulate intravascular FSS. Future directions include defining molecular programs mediating shear-adaptive survival through candidate panels assessing NRF2 oxidative stress targets, YAP/TEAD outputs, and NF-κB/survival regulators. Collectively, this work identifies NRF2-mediated shear adaptation as a potential mechanism driving metastasis in KRAS/STK11 LUAD and a targetable vulnerability in shear-tolerant tumor cells. Citation Format: Anna Showalter, Princess Rodriguez, David Joseph Seward, Paula B. Deming, Melissa Nicole Scheiber. STK11 loss enhances stress-adaptive programs supporting shear resilience in circulating tumor cells from KRAS-driven lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6104.
Showalter et al. (Fri,) studied this question.