Olfactory neuroblastoma (ONB) is a rare nasal tumor that is particularly devastating for patients. Advances in our understanding of ONB and its therapeutic vulnerabilities have been hindered by a lack of model systems to study it. Dr. Trudy Oliver’s lab in Duke’s Department of Pharmacology and Cancer Biology is known for creating novel genetically-engineered mouse models (GEMMs) of lung cancer. The Oliver Lab teamed up with Dr. Brad Goldstein, who is a surgeon-scientist at Duke, to focus on olfactory dysfunction and cancer. Together, their labs generated and characterized novel mouse models of ONB that have led to surprising new discoveries. Their study “Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small cell lung cancer” published in Cancer Cell was led by graduate students, Jack Finlay and Abbie Ireland, and technician, Bryony Hawgood. Their work reveals that ONB is highly similar to neuroendocrine cancers in other parts of the body, including small cell lung cancer (SCLC) and prostate neuroendocrine cancer, which has important implications for ONB diagnosis and treatment.
By employing alterations in Rb1/Trp53/Myc (RPM), Dr. Oliver’s team established a GEMM of high-grade metastatic ONB. Using this model, the team identified globose basal cells (GBCs) as a permissive cell of origin for ONB, revealing insights into the origins of ONB. Using lineage-tracing approaches, the authors found that ONB exhibited remarkable cell fate heterogeneity and plasticity, closely mimicking normal GBC developmental trajectories. Moreover, they found that ASCL1 is a key regulator of cell fate in ONB, whose depletion led to a new microvillar/tuft-cell-like fate, similar to microvillar cells that reside in the olfactory epithelium and tuft cells of the lung. Indeed, the Oliver and Goldstein labs found that mouse and human ONB were highly reminiscent of neuroendocrine lung tumors—in their intratumoral cell fate plasticity, immune-cold tumor microenvironment, and shared expression of therapeutic targets. Importantly, this study challenges existing paradigms in ONB classification, and may suggest that ONB should be considered for clinical trials designed to target SCLC and other neuroendocrine tumors.
This research was supported by the National Institutes of Health.