RACGAP1 defines a malignant proliferative niche and represents a therapeutic vulnerability in lung adenocarcinoma

The clinical management of lung adenocarcinoma (LUAD) is compromised by post-surgical recurrence and therapeutic resistance, underscoring the urgent need to uncover actionable therapeutic vulnerabilities. By integrating human genetics with multi-omics profiling and experimental validation, this study aims to systematically uncover critical molecular mediators of LUAD and delineate their therapeutic potential.

We implemented a multi-modal framework to identify and characterize causal LUAD therapeutic targets. We used two-sample Mendelian randomization (2SMR) to identify plasma proteins that are causally linked to LUAD risk. The lead candidate was then investigated using multi-omics to delineate its clinical relevance, cellular drivers, and tumor microenvironment. Oncogenic mechanisms were subsequently interrogated through functional experiments in LUAD models.

Our unbiased genetic screen identified Rac GTPase-activating protein 1 (RACGAP1) as a high-confidence causal risk factor for LUAD. Clinically, elevated RACGAP1 expression served as a robust, independent prognostic biomarker associated with poor survival across multiple cohorts. Single-cell profiling revealed that RACGAP1 defines a specific expanding epithelial subpopulation characterized by chromosomal instability (CIN) and apoptosis resistance. Spatially, these cells organize into "malignant proliferative niches" that drive tumor expansion. Mechanistically, RACGAP1 transcends its canonical role in cytokinesis to function as a pivotal oncogenic hub. It disables p53-mediated tumor suppression by upregulating MDM2, while concurrently activating the pro-survival PI3K/AKT and MEK/ERK signaling cascades. Crucially, pharmacological inhibition of these pathways abrogated the RACGAP1-driven malignant phenotypes, confirming the functional dependence of the tumor on this rewired signaling architecture.

This study presents genetic evidence supportive of a causal contribution of RACGAP1 to LUAD, highlighting it as a promising prognostic biomarker and candidate therapeutic target. By delineating a RACGAP1-driven axis that coordinates survival signaling and suppresses tumor surveillance, our findings highlight RACGAP1 as a promising therapeutic target for novel adjuvant strategies.