Single nucleus RNA profiling reveals potential therapeutic vulnerabilities in sinonasal carcinomas

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Sinonasal undifferentiated carcinomas (SNUC) are rare, aggressive tumors with limited therapeutic strategies.
• Recent discoveries identified molecular subgroups based on IDH2 mutations or SWI/SNF complex deficiencies, but their clinical implications are not fully understood.

Purpose of the Study:

• To investigate the distinct molecular and transcriptional states of IDH2-mutated (IDH2mt) and SMARCA4-mutated (SMARCA4mt) SNUC.
• To identify actionable therapeutic vulnerabilities in these rare tumor subtypes.

Main Methods:

• Single-nucleus RNA sequencing was performed on 12 FFPE SNUC samples (6 IDH2mt, 6 SMARCA4mt).
• Malignant cells were identified, and functional characterization was done using gene set enrichment analysis, pathway analysis, and transcription factor activity analysis.
• Druggable targets were explored, with spatial validation using immunohistochemistry and RNAscope.

Main Results:

• Four distinct malignant cell clusters were identified, including neuroendocrine-like, stress-adaptive, and EMT/TGF-β-driven programs.
• KIT was overexpressed in IDH2mt tumors, while MET was upregulated in SMARCA4mt tumors.
• Both subgroups showed elevated CDK4 and DDR1 expression, with spatial analysis revealing collagenolysis-dependent DDR1 activation.

Conclusions:

• IDH2mt and SMARCA4mt SNUC exhibit distinct transcriptional states and dependencies despite overlapping histology.
• Potential therapeutic strategies include targeting KIT, MET, CDK4/6, and DDR1, offering a framework for precision oncology in SNUC.