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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 15, 2024 |
| Title |
Olfactory neuroblastoma mimics molecular subtypes and lineage trajectories of small cell lung cancer [Single cell RNA seq on RPM and RPMA GBC-derived allograft tumors, CellTagged] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The olfactory epithelium relies on active neuron regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare, aggressive tumor of unclear origins. Here, we establish a new, highly-penetrant, genetically-engineered mouse model of ONB with alterations in Rb1/Trp53/Myc that exhibit a NEUROD1+ immature neuronal state. ASCL1 loss leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. We find ONB tumor heterogeneity to recapitulate developmental states of multipotent globose basal cells (GBCs), which our data demonstrate is a cell of origin for ONB. Similar to small cell lung cancer (SCLC), mouse and human ONB exhibit: mutually exclusive ASCL1, NEUROD1, and POU2F3- like states, an immune-cold tumor microenvironment, intratumoral subtype heterogeneity comprising neuronal and non-neuronal lineages, and subtype plasticity—as evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved developmental trajectories between ONB and SCLC subtypes with significant implications for ONB classification and treatment.
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| Overall design |
We harvested normal globose basal cells (GBCs) via immunomagnetic selection for KIT from the pooled olfactory epithelium of n=3-4 Rb1 fl/fl; Trp53 fl/fl; Myc T58A (RPM) or Rb1 fl/fl; Trp53 fl/fl; Myc T58A; Ascl1 fl/fl (RPMA) mice, not exposed to Cre, 10 days following methimazole lesioning. RPM and RPMA GBCs were transformed by treatment with Cre and transduced with a lentiviral barcode-based lineage-tracing technology termed CellTag V1 (established by Samantha Morris's lab, Kong et al., Nature Protocols, 2020). Transformed, CellTagged GBC's were implanted with Matrigel into the flanks of Scid/Beige mice. Upon outgrowth of the GBC-organoid-derived allografts, tumor cells were collected and processed for single-cell RNA sequencing. Allograft tumors were processed into single cell suspensions, and subject to 10X Genomics single-cell gene expression library construction (Dual-Index 3' GEX) followed by downstream Illumina-based sequencing.
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| Contributor(s) |
Ireland A, Oliver T |
| Citation(s) |
38788720 |
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| Submission date |
Sep 26, 2023 |
| Last update date |
Jul 28, 2024 |
| Contact name |
Trudy Oliver |
| E-mail(s) |
tgo@duke.edu, trudy.oliver@duke.edu
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| Phone |
6174607487
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| Organization name |
Duke University
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| Department |
Pharmacology & Cancer Biology
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| Lab |
theoliverlab
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| Street address |
Duke University, Box 3813, LSRC Room C138B, 308 Research Drive
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| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27708 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| This SubSeries is part of SuperSeries: |
| GSE244123 |
Olfactory neuroblastoma mimics molecular subtypes and lineage trajectories of small cell lung cancer |
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| Relations |
| BioProject |
PRJNA1021257 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE244119_RAW.tar |
335.0 Mb |
(http)(custom) |
TAR (of TAR) |
SRA Run Selector |
| Raw data are available in SRA |
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