Sinonasal undifferentiated carcinomas are rare and aggressive cancers that develop in the nasal cavity and surrounding sinuses. Because these tumors are uncommon and often resistant to standard therapies, treatment options remain limited. Researchers are now using single nucleus RNA sequencing to better understand these cancers at the cellular level and identify new opportunities for targeted treatment.

Researchers from LMU Munich, analyzed nearly 60,000 individual cell nuclei from 12 archived tumor samples representing two major molecular subtypes of sinonasal carcinoma. Using single nucleus RNA sequencing, they examined which genes were active in each cell, revealing important differences that are not visible using conventional laboratory techniques.

Single nucleus RNA sequencing (snRNA-seq) of IDH2mt and SMARCA4mt sinonasal carcinomas

a Cohort overview and schematic workflow display the sample preparation for snRNA-seq. b UMAP visualization of the filtered cohort of 59,612 cells stratified by mutation status (IDH2 mutated (IDH2mt), SMARCA4 mutated (SMARCA4mt)) and colored by cell cluster. IDH2mt and SMARCA4mt snRNA-seq profiles showed a joined single-cell landscape with prevalence of all major stromal and immune cell types. c Relative RNA abundance of non-malignant cells to the total non-malignant population for each of the 12 samples is plotted. d A heatmap of large-scale copy number variations for individual tumor cell nuclei (rows) is inferred from snRNA-seq data. For the visualization, each sample was downsampled to the size of the smallest sample (338 malignant cells).

The team identified 17 different cell types within the tumors, including four distinct groups of malignant cells. Each malignant group displayed unique biological characteristics. Some cells showed neuroendocrine features, others exhibited stress response and extracellular matrix remodeling, while another group displayed signatures associated with epithelial to mesenchymal transition, a process often linked to cancer progression and metastasis.

The analysis also uncovered several proteins that could serve as potential therapeutic targets. Tumors carrying IDH2 mutations showed elevated expression of KIT, while tumors with SMARCA4 mutations exhibited increased MET expression. Both tumor types also expressed high levels of CDK4 and DDR1, suggesting that drugs targeting these molecules may provide new treatment options.

One particularly interesting finding involved DDR1, a receptor that interacts with collagen in the tumor microenvironment. The researchers found evidence that collagen remodeling within specific tumor regions may activate DDR1 signaling, potentially creating a vulnerability that could be exploited with targeted therapies.

Although additional laboratory and clinical studies will be needed to confirm these findings, the work demonstrates how single nucleus RNA sequencing can uncover important biological differences between tumors that appear very similar under the microscope. By identifying the molecular pathways that drive each subtype, researchers can begin matching patients with therapies that are more likely to be effective.

As precision oncology continues to advance, high resolution RNA sequencing technologies are providing valuable insight into rare cancers that have historically been difficult to study. Understanding the unique cellular programs within these tumors may ultimately lead to more personalized and effective treatments for patients with sinonasal carcinoma.