A cilia-associated epithelial alteration axis nominates ERICH3 as an entry point to PI3K engagement in lung adenocarcinoma

Abstract

LUAD adopts heterogeneous oncogenic signalling states, and bias toward a PI3K–AKT–mTOR–engaged state is not fully explained by canonical pathway lesions. Because membrane-proximal spatial organization can tune receptor-proximal signalling yet is difficult to quantify in human tumours, we used cilia-associated epithelial programs as a hypothesis-generating entry point to identify convergently perturbed candidates and evaluate their relationship with PI3K engagement. We performed intersection-based multi-omic prioritization in TCGA-LUAD, evaluated dependency directionality using DepMap/CCLE expression with CRISPR dependency profiles, and tested the functional relationship between ERICH3 loss and PI3K engagement by siRNA perturbation with PI3K-inhibitor rescue. We anchored tumour context using bulk co-expression, spatial transcriptomics, and single-cell analyses with ERICH3 stratified by transcript “detection”, complemented by CellChat-based communication inference and structure/variant-informed hypothesis nomination. ERICH3 was prioritized through a cilia-informed screen as a convergently attenuated candidate, showed reduced protein in paired LUAD specimens (16/24, 66.7%; P = 0.014), promoter hypermethylation, and favourable survival association. An external DepMap dependency screen nominated PI3K–AKT–mTOR dependency directionality in ERICH3 -low contexts (Hallmark NES = − 1.79; P = 1.04 × 10⁻ 4 ), which was subsequently evaluated functionally in LUAD cell lines. In LUAD cell lines, ERICH3 knockdown increased PI3K–AKT–mTOR phosphorylation and malignant phenotypes, which were attenuated by PI3K inhibition, supporting a functional relationship between ERICH3 loss and PI3K pathway engagement. Multi-scale transcriptomic analyses showed that ERICH3 transcripts were detected predominantly in a mucous epithelial compartment and non-tumour epithelium; CellChat suggested hypothesis-generating immune-interaction signals associated with ERICH3 -detected mucous cells. Structural modelling and tumour-variant mapping nominated discrete membrane-proximal regions for mechanism-discriminating follow-up. Our findings support a testable model in which attenuation of ERICH3, identified through a cilia-informed epithelial framework, is associated with a PI3K-engaged malignant state in LUAD. The present study does not establish that ERICH3 directly regulates primary-cilium formation, ciliary protein localization, or ligand-induced ciliary signalling; the precise upstream membrane-proximal and/or cilia-related route remains to be defined.