Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer Journal Article
| Authors: | Finlay, J. B.; Ireland, A. S.; Hawgood, S. B.; Reyes, T.; Ko, T.; Olsen, R. R.; Abi Hachem, R.; Jang, D. W.; Bell, D.; Chan, J. M.; Goldstein, B. J.; Oliver, T. G. |
| Article Title: | Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer |
| Abstract: | 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. © 2024 The Author(s) |
| Keywords: | immunohistochemistry; adult; controlled study; genetics; histopathology; nonhuman; animal cell; mouse; phenotype; animal; metabolism; animals; mice; animal tissue; lung neoplasms; animal experiment; animal model; basic helix-loop-helix transcription factors; cell fate; pathology; cell population; transcriptomics; protein p53; carcinogenesis; cell lineage; stem cell; disease model; lung tumor; basal cell; chromatin; tumor suppressor protein p53; cervical lymph node; disease models, animal; esthesioneuroblastoma; esthesioneuroblastoma, olfactory; nerve regeneration; nose tumor; nose neoplasms; sensory nerve cell; olfactory bulb; small cell lung cancer; small cell lung carcinoma; basic helix loop helix transcription factor; nose cavity; neuroendocrine; plasticity; tumor microenvironment; sclc; thiamazole; perikaryon; olfactory cortex; olfactory neuroblastoma; RPM; humans; human; male; article; evaluation study; rna sequencing; hierarchical clustering; differential gene expression; genetically engineered mouse strain; olfactory epithelium; ascl1; neurod1; pou2f3; tuft; olfactory mucosa; ascl1 protein, human; ascl1 protein, mouse; nasal tissue; olfactory ensheathing cell; trigeminus ganglion |
| Journal Title: | Cancer Cell |
| Volume: | 42 |
| Issue: | 6 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2024-06-10 |
| Start Page: | 1086 |
| End Page: | 1105.e13 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2024.05.003 |
| PUBMED: | 38788720 |
| PROVIDER: | scopus |
| PMCID: | PMC11186085 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
