%0 Journal Article
%T Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer.
%A Finlay JB
%A Ireland AS
%A Hawgood SB
%A Reyes T
%A Ko T
%A Olsen RR
%A Abi Hachem R
%A Jang DW
%A Bell D
%A Chan JM
%A Goldstein BJ
%A Oliver TG
%J Cancer Cell
%V 42
%N 6
%D 2024 Jun 10
%M 38788720
%F 38.585
%R 10.1016/j.ccell.2024.05.003
%X 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.