LLPS-Driven Membraneless Organelle Activity Landscape Reveals Molecular Subtypes, Immune States, and Prognostic Stratification in Lung Adenocarcinoma
- 1Department of Radiation Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China
- 2Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, Guangzhou 510165, China
- 3Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
Abstract
Liquid–liquid phase separation (LLPS) drives the formation of membraneless organelles (MLOs) that regulate cellular compartmentalization and diverse biological processes. However, the landscape and clinical relevance of MLO-associated activity in lung adenocarcinoma (LUAD) remain unclear. We integrated curated MLO-associated gene sets with transcriptomic data to estimate MLO activity using single-sample gene set enrichment analysis. MLO-related molecular subtypes were identified via consensus clustering, and an integrative machine learning framework was used to develop and validate the Membraneless Organelle Risk Score (MLORS) across independent cohorts. We further examined associations of MLORS with immune features, genomic alterations, and predicted treatment sensitivity and evaluated the function and phase-separation properties of E2F7 in vitro. MLO-associated activity was broadly dysregulated in LUAD, with high-MLO and low-MLO subtypes exhibiting distinct immune profiles and survival outcomes. High MLORS was associated with poorer survival, a computationally inferred immune-suppressed microenvironmental profile, higher tumor mutational burden, and lower predicted sensitivity to selected EGFR-targeted agents and chemotherapy. E2F7 formed nuclear condensates with LLPS-like properties and promoted lung cancer cell proliferation and migration in vitro. These findings link transcriptionally inferred MLO activity to the heterogeneity and prognosis of LUAD, support MLORS as a candidate prognostic stratification tool, and identify E2F7 phase-separation behavior as a potential therapeutic vulnerability.
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BibTeX
@article{yan2026llpsdriven,
title = {{LLPS-Driven Membraneless Organelle Activity Landscape Reveals Molecular Subtypes, Immune States, and Prognostic Stratification in Lung Adenocarcinoma}},
author = {Hongmei Yan and Nanyan Yang and Lu Zhang and Haorui Tian and Wei Mo and Maoying Lan and Zilong Lin and Hantan Lin and Zeyu Wang and Juntao Zou and Fen He and Jiancong Sun},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272110008},
url = {https://www.mdpi.com/1422-0067/27/21/10008},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - LLPS-Driven Membraneless Organelle Activity Landscape Reveals Molecular Subtypes, Immune States, and Prognostic Stratification in Lung Adenocarcinoma
AU - Hongmei Yan
AU - Nanyan Yang
AU - Lu Zhang
AU - Haorui Tian
AU - Wei Mo
AU - Maoying Lan
AU - Zilong Lin
AU - Hantan Lin
AU - Zeyu Wang
AU - Juntao Zou
AU - Fen He
AU - Jiancong Sun
PY - 2026
DA - 2026/11/08
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272110008
UR - https://www.mdpi.com/1422-0067/27/21/10008
AB - Liquid–liquid phase separation (LLPS) drives the formation of membraneless organelles (MLOs) that regulate cellular compartmentalization and diverse biological processes. However, the landscape and clinical relevance of MLO-associated activity in lung adenocarcinoma (LUAD) remain unclear. We integrated curated MLO-associated gene sets with transcriptomic data to estimate MLO activity using single-sample gene set enrichment analysis. MLO-related molecular subtypes were identified via consensus clustering, and an integrative machine learning framework was used to develop and validate the Membraneless Organelle Risk Score (MLORS) across independent cohorts. We further examined associations of MLORS with immune features, genomic alterations, and predicted treatment sensitivity and evaluated the function and phase-separation properties of E2F7 in vitro. MLO-associated activity was broadly dysregulated in LUAD, with high-MLO and low-MLO subtypes exhibiting distinct immune profiles and survival outcomes. High MLORS was associated with poorer survival, a computationally inferred immune-suppressed microenvironmental profile, higher tumor mutational burden, and lower predicted sensitivity to selected EGFR-targeted agents and chemotherapy. E2F7 formed nuclear condensates with LLPS-like properties and promoted lung cancer cell proliferation and migration in vitro. These findings link transcriptionally inferred MLO activity to the heterogeneity and prognosis of LUAD, support MLORS as a candidate prognostic stratification tool, and identify E2F7 phase-separation behavior as a potential therapeutic vulnerability.
SN - 1422-0067
ER -