What question did this study set out to answer?

This research aims to understand how STK11 loss affects the resilience of circulating tumor cells under mechanical stress in lung adenocarcinoma.

April 5, 2026

Abstract 6104: STK11 loss enhances stress-adaptive programs supporting shear resilience in circulating tumor cells from KRAS-driven lung adenocarcinoma

Key Points

This research aims to understand how STK11 loss affects the resilience of circulating tumor cells under mechanical stress in lung adenocarcinoma.
Used embryonic zebrafish xenograft model with KRAS-mutant and STK11-null lung adenocarcinoma cells.
Conducted longitudinal imaging of circulating tumor cell behavior in physiological circulation.
Analyzed RNA sequencing data under glutamine deprivation to assess stress response pathways.
Developed an FSS-specific gene panel to identify shear-adaptive programs.
STK11-null cells showed a higher micrometastatic burden and increased extravasation compared to parental controls.
RNA-seq analysis revealed enrichment of oxidative stress and stimulus-response pathways.
Identified NRF2-mediated antioxidant responses as crucial for shear adaptation in tumor cells.

Abstract

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.

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Cite This Study

Showalter et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fd3da79560c99a0a3234 https://doi.org/https://doi.org/10.1158/1538-7445.am2026-6104

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