NEW YORK – A research team from China has used single-cell transcriptome sequencing to explore the origins and heterogeneity of olfactory neuroblastoma, as well as the tumor microenvironment and molecular subtypes associated with the rare nasal cavity cancer.
"By integrating our findings, we identified an uncharacterized malignant cell subtype with distinct transcriptomic performance as well as several drug-targeted functional pathways of [olfactory neuroblastoma] cellular components, which provide news insights and can potentially inspire new diagnostic and therapeutic strategies for this rare malignancy," senior and corresponding author Hongmeng Yu, a researcher at Fudan University, and colleagues wrote in Nature Cancer on Thursday.
Past research suggests that some 40 percent of olfactory neuroblastoma patients remain disease-free after five years, with an overall survival rate of 50 percent after 10 years. Even so, the rarity of the cancer — which accounts for just 5 to 6 percent of sinus and nasal cancers overall — has made it difficult to untangle molecular features that may help in improving patient outcomes.
With that in mind, the team turned to single-cell RNA sequencing to assess expression profiles in 85,452 individual cells from 10 olfactory neuroblastoma tumors and 10,873 cells from a cancer-free olfactory mucosa sample. They unearthed tumor and tumor microenvironment clusters offering clues to their molecular features and potential vulnerabilities.
"Recently, [olfactory neuroblastoma] was proposed to arise from the olfactory mucosa (OM) in the nasal cleft," the authors explained, "although the precise cellular component of olfactory epithelium from which [olfactory neuroblastoma] is generated remains to be elucidated."
In addition to five expression groups they found within individual tumors, the investigators described three expression-based subtypes for olfactory neuroblastoma. These were subsequently corroborated using additional single-cell RNA-seq, bulk RNA-seq, and quantitative immunohistochemistry analyses on 30 olfactory neuroblastoma samples.
Two of the tumor clusters contained basal and neural signatures resembling those reported in the past, the team explained. But the analyses also highlighted a previously unappreciated group of olfactory neuroblastoma tumors with mesenchymal expression features.
"In the present scRNA-seq study, neural and basal signature-based classification was not suitable for identifying all malignant [olfactory neuroblastoma] cells, as a few tumor subgroups remained undefined," the authors wrote, noting that "undescribed cells exhibited mesenchymal signatures and were then matched to olfactory [horizontal basal cells] or sustentacular cells by pathway enrichment and correlation analysis."
While olfactory neuroblastoma tumors of the neural subtype were marked by CHG protein expression, the Ki-67 protein marker coincided with the basal subtype. The researchers also linked expression of the CTGF protein and the CCN2 gene coding for it to the mesenchymal subtype of olfactory neuroblastoma.
Despite the limited number of tumor samples analyzed for the study, the investigators also delved into tumor or tumor microenvironment features, such as biomarkers or immune cell interactions, that might coincide with olfactory neuroblastoma patient responses to specific chemotherapy regimens.
The study's authors noted that further research will be needed to explore the possibility that olfactory neuroblastoma subtypes stem from distinct or shared cell types in the olfactory mucosa. In addition, they cautioned that "although [olfactory neuroblastomas] genetically resemble the olfactory mucosa, the origin of the tumor is still unknown because of a lack of experimental [olfactory neuroblastoma] models."