Scholarlink

Background <p>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.</p> Methods <p>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 <i>ERICH3</i> 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 <i>ERICH3</i> stratified by transcript “detection”, complemented by CellChat-based communication inference and structure/variant-informed hypothesis nomination.</p> Results <p><i>ERICH3</i> was prioritized through a cilia-informed screen as a convergently attenuated candidate, showed reduced protein in paired LUAD specimens (16/24, 66.7%; <i>P</i> = 0.014), promoter hypermethylation, and favourable survival association. An external DepMap dependency screen nominated PI3K–AKT–mTOR dependency directionality in <i>ERICH3</i>-low contexts (Hallmark <i>NES</i> = − 1.79; <i>P</i> = 1.04 × 10⁻<sup>4</sup>), which was subsequently evaluated functionally in LUAD cell lines.</p> <p>In LUAD cell lines, <i>ERICH3</i> 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 <i>ERICH3</i>-detected mucous cells. Structural modelling and tumour-variant mapping nominated discrete membrane-proximal regions for mechanism-discriminating follow-up.</p> Conclusions <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月3日

查看全文
  • Qiang Chen,
  • Yixuan Wang,
  • Yang Zhang,
  • Shuo Ying,
  • Huazhuo Feng,
  • Kai Hou,
  • Li Zhang,
  • Xuexia Zhou,
  • Xuebing Li,
  • Jianwen Qin,
  • Dingzhi Huang

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.