Olfactory neuroblastoma (ONB), a rare malignant tumor arising from the olfactory epithelium, remains poorly understood. A recent study using genetically engineered mouse models sheds light on the origins and behavior of ONB, offering new avenues for treatment and classification.
The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity—evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.
Tumor Model Development: Researchers established a mouse model with Rb1/Trp53/Myc (RPM) alterations, simulating high-grade metastatic ONB. This model exhibits a NEUROD1+ immature neuronal phenotype.
Cell of Origin: Globose basal cells (GBCs) were identified as a permissive cell of origin for ONB, reflecting normal GBC developmental pathways.
Intratumoral Heterogeneity: ONBs show significant cell fate heterogeneity and lineage plasticity, mirroring developmental trajectories of GBCs.
Role of ASCL1: Loss of ASCL1 in RPM ONB led to the emergence of non-neuronal histopathologies, including POU2F3+ microvillar-like states.
Comparative Analysis: ONBs share transcriptional similarities with neuroendocrine tumors like small-cell lung cancer (SCLC), with mutually exclusive NEUROD1 and POU2F3-like states and an immune-cold tumor microenvironment.
Implications:
This study highlights conserved similarities between ONB and neuroendocrine tumors, providing crucial insights for ONB classification and potential therapeutic strategies.
Finlay, J. B., Ireland, A. S., Hawgood, S. B., Reyes, T., Ko, T., Olsen, R. R., … Oliver, T. G. (2024). Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer. Cancer Cell, 42(6), 1086-1105.e13. doi:10.1016/j.ccell.2024.05.003
