Tumor suppressors in Sox2-mediated lung cancers promote distinct cell-intrinsic and immunologic remodeling

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Non-small cell lung cancer (NSCLC) comprises lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).
• TP53 and PTEN alterations are frequent in NSCLC, but their interplay with SOX2 remains unclear.
• Understanding these genetic interactions is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the cooperative roles of Trp53 and Pten loss with SOX2 in NSCLC pathogenesis.
• To characterize the impact of these genetic alterations on tumor progression, histology, and the immune microenvironment.
• To identify potential therapeutic vulnerabilities in SOX2-driven NSCLC.

Main Methods:

• Genetically engineered mouse models (GEMMs) with specific gene deletions (Trp53, Pten) on a Sox2hi background.
• Histological analysis and single-cell RNA sequencing (scRNA-seq) to assess tumor characteristics.
• In vivo experiments involving complement factor B knockout (Cfb-/-) to evaluate survival.

Main Results:

• Loss of Trp53 or Pten in Sox2-driven models led to reduced survival and increased tumor burden.
• Tumor histology shifted towards LUAD or retained LUSC morphology depending on the specific genetic loss.
• A CD38+ inflammatory monocyte sub-cluster was identified, associated with complement pathway activation, and Complement Factor B (CFB) correlated with poor LUSC patient survival.

Conclusions:

• Trp53 and Pten act cooperatively with SOX2 to promote NSCLC progression, influencing mucin composition and immune cell infiltration.
• Targeting the complement pathway, specifically CFB, may represent a novel therapeutic strategy for LUSC.
• These findings elucidate key molecular mechanisms in SOX2-driven NSCLC and highlight potential avenues for treatment.