Targeting Pan-Cancer Stemness: Core Regulatory lncRNAs as Novel Therapeutic Vulnerabilities

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Tumor stemness is crucial for cancer progression and therapy resistance.
• Long non-coding RNAs (lncRNAs) are implicated in regulating tumor stemness.
• Understanding lncRNA roles is vital for developing new cancer treatments.

Purpose of the Study:

• To systematically investigate the regulatory roles of lncRNAs in tumor stemness.
• To identify lncRNA signatures associated with stemness across various cancer types.
• To develop a prognostic model based on lncRNA expression for predicting patient outcomes.

Main Methods:

• Integration of The Cancer Genome Atlas (TCGA) bulk transcriptomic data with pan-cancer single-cell atlases.
• Application of machine-learning-based stemness metrics to quantify stemness features.
• Construction of a prognostic model using identified lncRNA gene sets.

Main Results:

• Identified cancer-type-specific lncRNA gene sets associated with stemness.
• High-stemness subtypes showed increased proliferation, immunosuppression, and metabolic reprogramming.
• Developed a robust prognostic model with high predictive performance across multiple cancers.
• Reconstructed stemness evolution trajectories at single-cell resolution, revealing CSC-specific patterns.
• Consistently nominated core regulatory lncRNAs, including NEAT1 and MALAT1.

Conclusions:

• lncRNAs play significant roles in driving tumor stemness, progression, and resistance.
• NEAT1 and MALAT1 are key regulatory lncRNAs in cancer stemness.
• The study provides a framework for understanding lncRNA-driven cancer aggressiveness and identifies potential therapeutic targets.