Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer
- Cancer Cell. 2024 May 23:S1535-6108(24)00164-8. doi: 10.1016/j.ccell.2024.05.003.
- 1. Department of Head and Neck Surgery & Communication Sciences, Duke University, Durham 27710, NC, USA.
- 2. Department of Pharmacology and Cancer Biology, Duke University, Durham 27710, NC, USA.
- 3. Department of Pharmacology and Cancer Biology, Duke University, Durham 27710, NC, USA; Department of Oncological Sciences, University of Utah, Salt Lake City 84112, UT, USA.
- 4. Department of Oncological Sciences, University of Utah, Salt Lake City 84112, UT, USA.
- 5. Division of Anatomic Pathology, City of Hope Comprehensive Cancer Center, Duarte 91010, CA, USA.
- 6. Human Oncology and Pathogenesis Program, Memorial-Sloan Kettering Cancer Center, New York City 10065, NY, USA.
- 7. Department of Head and Neck Surgery & Communication Sciences, Duke University, Durham 27710, NC, USA; Department of Neurobiology, Duke University, Durham 27710, NC, USA. Electronic address: [email protected].
- 8. Department of Pharmacology and Cancer Biology, Duke University, Durham 27710, NC, USA; Department of Oncological Sciences, University of Utah, Salt Lake City 84112, UT, USA. Electronic address: [email protected].
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.