Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer.
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.
Pubmed ID: 38788720 RIS Download
Research resources used in this publication
- B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (RRID:IMSR_JAX:007909) (organism)
- B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (RRID:IMSR_JAX:007909) (organism)
- HEK293T/17 (RRID:CVCL_1926) (cell line)
-
STOCK Igs2tm1(CAG-Myc*T58A/luc)Wrey Trp53
-
C.B-Igh-1b/GbmsTac-Prkdcscid-Lyst
- pSMAL-CellTag-V1 (RRID:Addgene_115643) (plasmid)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- CD45 - BSA and azide free (RRID:AB_2864384)
- Ki-67 (D3B5) (Alexa Fluor® 647 Conjugate) (RRID:AB_2728830)
- Alexa Fluor(R) 594 anti-Tubulin Beta 3 (TUBB3) (RRID:AB_2565285)
- Peroxidase-AffiniPure Goat Anti-Mouse IgG, Fc_ Subclass 1 Specific (min X Hu,Bov,Rb Sr Prot) (RRID:AB_2338513)
- Peroxidase-AffiniPure Donkey Anti-Rabbit IgG (H+L) (RRID:AB_10015282)
- YAP (D8H1X) XP Rabbit mAb (RRID:AB_2650491)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492)
- Synaptophysin (D8F6H) XP® Rabbit mAb (RRID:AB_2799098)
- Anti-SOX9 antibody (RRID:AB_2728660)
- Rabbit Anti-P-CK Polyclonal Antibody, Unconjugated (RRID:AB_10855057)
- Rabbit Anti-TTF1 Monoclonal Antibody, Unconjugated, Clone EP1584Y (RRID:AB_1310784)
- Sox2 (C70B1) Rabbit mAb (IHC Preferred) (RRID:AB_2194037)
- Goat Anti-Human Neurod1 Polyclonal antibody, Unconjugated (RRID:AB_2149217)
- NeuroD (D35G2) Rabbit mAb (RRID:AB_10549071)
- Mouse Anti-S100 Monoclonal Antibody, Unconjugated, Clone 4C4.9 (RRID:AB_304258)
- NeuroD1 antibody [EPR4008] (RRID:AB_10861489)
- Goat Anti-Human Ncam-1 / cd56 Polyclonal antibody, Unconjugated (RRID:AB_442152)
- Anti-POU2F3 antibody produced in rabbit (RRID:AB_1855585)
- anti-LHX2 (RRID:AB_2722523)
- Ki-67 Pure B56 100ug (RRID:AB_396287)
- Anti-mCherry (RRID:AB_2861426)
- Goat Anti-Human Tp63 / tp73l Polyclonal antibody, Unconjugated (RRID:AB_2207174)
- Chromogranin A Antibody (RRID:AB_789299)
- Anti-Calcitonin Gene Related Peptide antibody produced in rabbit (RRID:AB_259091)
- Anti-CD3 antibody (RRID:AB_305055)
- Recombinant Anti-CD11b antibody [EPR1344] (RRID:AB_2650514)
- Neuronal Class III beta-Tubulin (TUJ1) Monoclonal Antibody, Purified (RRID:AB_2313773)
- Anti-beta III Tubulin antibody - Neuronal Marker (RRID:AB_444319)
- Recombinant Anti-MASH1/Achaete-scute homolog 1 antibody [EPR19840] (RRID:AB_2924270)
- HES1 (D6P2U) (RRID:AB_2728766)
- CD117 (c-Kit) Monoclonal Antibody (2B8), APC, eBioscience (RRID:AB_469430)
- Rabbit Anti-c-Kit Monoclonal Antibody, Unconjugated, Clone D13A2 (RRID:AB_1147633)
Associated grants
- Agency: NIDCD NIH HHS, United States
Id: R01 DC016859 - Agency: NCI NIH HHS, United States
Id: U24 CA213274 - Agency: NCI NIH HHS, United States
Id: K08 CA259161 - Agency: NCI NIH HHS, United States
Id: K12 CA167540 - Agency: NCI NIH HHS, United States
Id: U01 CA231844 - Agency: NCI NIH HHS, United States
Id: P30 CA008748 - Agency: NCI NIH HHS, United States
Id: F31 CA275295 - Agency: NIDCD NIH HHS, United States
Id: F30 DC021348 - Agency: NCI NIH HHS, United States
Id: P30 CA014236 - Agency: NCI NIH HHS, United States
Id: UM1 CA239755
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This is a list of tools and resources that we have found mentioned in this publication.
CD45 - BSA and azide free (antibody)
RRID:AB_2864384
This monoclonal targets CD45
View all literature mentionsKi-67 (D3B5) (Alexa Fluor® 647 Conjugate) (antibody)
RRID:AB_2728830
This monoclonal targets Ki-67
View all literature mentionsAlexa Fluor(R) 594 anti-Tubulin Beta 3 (TUBB3) (antibody)
RRID:AB_2565285
This monoclonal targets Tubulin beta-3
View all literature mentionsPeroxidase-AffiniPure Goat Anti-Mouse IgG, Fc_ Subclass 1 Specific (min X Hu,Bov,Rb Sr Prot) (antibody)
RRID:AB_2338513
This unknown targets Mouse IgG, Fc? Subclass 1 Specific
View all literature mentionsPeroxidase-AffiniPure Donkey Anti-Rabbit IgG (H+L) (antibody)
RRID:AB_10015282
This polyclonal targets IgG (H+L)
View all literature mentionsYAP (D8H1X) XP Rabbit mAb (antibody)
RRID:AB_2650491
This recombinant monoclonal targets YAP
View all literature mentionsSox9 (D8G8H) Rabbit mAb #82630 (antibody)
RRID:AB_2665492
This monoclonal targets Sox9
View all literature mentionsSynaptophysin (D8F6H) XP® Rabbit mAb (antibody)
RRID:AB_2799098
This monoclonal targets SYP
View all literature mentionsAnti-SOX9 antibody (antibody)
RRID:AB_2728660
This monoclonal targets SOX9
View all literature mentionsRabbit Anti-P-CK Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_10855057
This polyclonal targets Rabbit P-CK
View all literature mentionsRabbit Anti-TTF1 Monoclonal Antibody, Unconjugated, Clone EP1584Y (antibody)
RRID:AB_1310784
This monoclonal targets TTF1
View all literature mentionsSox2 (C70B1) Rabbit mAb (IHC Preferred) (antibody)
RRID:AB_2194037
This monoclonal targets Sox2 (C70B1)
View all literature mentionsGoat Anti-Human Neurod1 Polyclonal antibody, Unconjugated (antibody)
RRID:AB_2149217
This polyclonal targets Human NeuroD1
View all literature mentionsNeuroD (D35G2) Rabbit mAb (antibody)
RRID:AB_10549071
This monoclonal targets NEUROD1
View all literature mentionsMouse Anti-S100 Monoclonal Antibody, Unconjugated, Clone 4C4.9 (antibody)
RRID:AB_304258
This monoclonal targets S100
View all literature mentionsNeuroD1 antibody [EPR4008] (antibody)
RRID:AB_10861489
This monoclonal targets NeuroD1 antibody [EPR4008]
View all literature mentionsGoat Anti-Human Ncam-1 / cd56 Polyclonal antibody, Unconjugated (antibody)
RRID:AB_442152
This polyclonal targets Human NCAM-1 / CD56
View all literature mentionsAnti-POU2F3 antibody produced in rabbit (antibody)
RRID:AB_1855585
This unknown targets Human POU2F3
View all literature mentionsKi-67 Pure B56 100ug (antibody)
RRID:AB_396287
This monoclonal targets Ki-67
View all literature mentionsAnti-mCherry (antibody)
RRID:AB_2861426
This polyclonal targets mCherry
View all literature mentionsGoat Anti-Human Tp63 / tp73l Polyclonal antibody, Unconjugated (antibody)
RRID:AB_2207174
This polyclonal targets Human TP63 / TP73L
View all literature mentionsChromogranin A Antibody (antibody)
RRID:AB_789299
This polyclonal targets Human Chromogranin A
View all literature mentionsAnti-Calcitonin Gene Related Peptide antibody produced in rabbit (antibody)
RRID:AB_259091
This polyclonal targets Calcitonin Gene Related Peptide antibody produced in rabbit
View all literature mentionsAnti-CD3 antibody (antibody)
RRID:AB_305055
This polyclonal targets CD3
View all literature mentionsRecombinant Anti-CD11b antibody [EPR1344] (antibody)
RRID:AB_2650514
This recombinant monoclonal targets CD11b
View all literature mentionsNeuronal Class III beta-Tubulin (TUJ1) Monoclonal Antibody, Purified (antibody)
RRID:AB_2313773
This monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsAnti-beta III Tubulin antibody - Neuronal Marker (antibody)
RRID:AB_444319
This polyclonal targets beta III Tubulin
View all literature mentionsRecombinant Anti-MASH1/Achaete-scute homolog 1 antibody [EPR19840] (antibody)
RRID:AB_2924270
This recombinant monoclonal targets MASH1
View all literature mentionsCD117 (c-Kit) Monoclonal Antibody (2B8), APC, eBioscience (antibody)
RRID:AB_469430
This monoclonal targets CD117 (c-Kit)
View all literature mentionsRabbit Anti-c-Kit Monoclonal Antibody, Unconjugated, Clone D13A2 (antibody)
RRID:AB_1147633
This monoclonal targets c-Kit
View all literature mentionsB6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (organism)
RRID:IMSR_JAX:007909
Mus musculus with name B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J from IMSR.
View all literature mentionsB6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J (organism)
RRID:IMSR_JAX:007909
Mus musculus with name B6.Cg-Gt(ROSA)26Sortm9(CAG-tdTomato)Hze/J from IMSR.
View all literature mentionsHEK293T/17 (cell line)
RRID:CVCL_1926
Cell line HEK293T/17 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentions
STOCK Igs2tm1(CAG-Myc*T58A/luc)Wrey Trp53 Rb1/OlvrJ (organism)
RRID:IMSR_JAX:029971
Mus musculus with name STOCK Igs2tm1(CAG-Myc*T58A/luc)Wrey Trp53
C.B-Igh-1b/GbmsTac-Prkdcscid-Lyst N7 (organism)
RRID:IMSR_TAC:CBSCBG
Mus musculus with name C.B-Igh-1b/GbmsTac-Prkdcscid-Lyst
