1. Academic Validation
  2. Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer

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.
John B Finlay 1 Abbie S Ireland 2 Sarah B Hawgood 2 Tony Reyes 3 Tiffany Ko 1 Rachelle R Olsen 4 Ralph Abi Hachem 1 David W Jang 1 Diana Bell 5 Joseph M Chan 6 Bradley J Goldstein 7 Trudy G Oliver 8
Affiliations

Affiliations

  • 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].
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.

Keywords

ASCL1; NEUROD1; POU2F3; RPM; SCLC; esthesioneuroblastoma; neuroendocrine; olfactory neuroblastoma; plasticity; tuft.

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