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ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES
Pineoblastoma (PB), a rare and aggressive brain tumor affecting children, presents with a highly variable age distribution and treatment outcome. Our recent bulk tumor analyses of DNA methylation and mutational landscapes uncovered four discrete PB molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/F...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260074/ http://dx.doi.org/10.1093/neuonc/noad073.008 |
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author | Gudenas, Brian Englinger, Bernhard Liu, Anthony P Y Ahmad, Sheikh Tanveer Meredith, David Pfaff, Elke Paul, Leena Hadley, Jennifer Batts, Melissa Klimo Jr., Paul Boop, Frederick A Gajjar, Amar Robinson, Giles W Orr, Brent A Lin, Hong Alexandrescu, Sanda Jones, David T W Filbin, Mariella G Northcott, Paul A |
author_facet | Gudenas, Brian Englinger, Bernhard Liu, Anthony P Y Ahmad, Sheikh Tanveer Meredith, David Pfaff, Elke Paul, Leena Hadley, Jennifer Batts, Melissa Klimo Jr., Paul Boop, Frederick A Gajjar, Amar Robinson, Giles W Orr, Brent A Lin, Hong Alexandrescu, Sanda Jones, David T W Filbin, Mariella G Northcott, Paul A |
author_sort | Gudenas, Brian |
collection | PubMed |
description | Pineoblastoma (PB), a rare and aggressive brain tumor affecting children, presents with a highly variable age distribution and treatment outcome. Our recent bulk tumor analyses of DNA methylation and mutational landscapes uncovered four discrete PB molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB), providing a major advance in our understanding of biological and clinical heterogeneity. However, developmental origins of PB subgroup heterogeneity and mechanisms governing how specific genetic alterations promote malignancy remain unknown. We conducted single-nucleus RNA sequencing of 38 primary tumors, including cases from all subgroups, to uncover intra-tumoral heterogeneity, developmental origins and expose selective dependencies. Transcriptional programs driving intra-tumoral heterogeneity showed subgroup-specific patterns such as mRNA splicing associated with PB-miRNA1/2 and phototransduction in PB-RB and PB-MYC/FOXR2. Next, we created a single-cell transcriptional atlas of the murine pineal gland across 11 developmental stages and found significant associations between PB subgroups and specific differentiation states of the pinealocyte lineage, suggesting subgroup-specific developmental origins. Characterization of pineal development informed generation of biologically faithful disease models, including a novel genetically engineered mouse model of the PB-RB subgroup. PB-Rb1 mouse tumors were histologically and molecularly validated for their fidelity to human tumor counterparts, exhibiting up-regulation of key pinealocyte lineage markers that are diagnostic in patients. Using cell lines derived from our PB-Rb1 mouse model we identified several transcription factor dependencies we believe are high-jacked during normal pinealocyte development. Our findings inform the developmental origins of pineoblastoma as well as provides candidates for potential therapeutic targets. |
format | Online Article Text |
id | pubmed-10260074 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102600742023-06-13 ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES Gudenas, Brian Englinger, Bernhard Liu, Anthony P Y Ahmad, Sheikh Tanveer Meredith, David Pfaff, Elke Paul, Leena Hadley, Jennifer Batts, Melissa Klimo Jr., Paul Boop, Frederick A Gajjar, Amar Robinson, Giles W Orr, Brent A Lin, Hong Alexandrescu, Sanda Jones, David T W Filbin, Mariella G Northcott, Paul A Neuro Oncol Final Category: ATRT/Embryonal/ETMR - ATRT Pineoblastoma (PB), a rare and aggressive brain tumor affecting children, presents with a highly variable age distribution and treatment outcome. Our recent bulk tumor analyses of DNA methylation and mutational landscapes uncovered four discrete PB molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB), providing a major advance in our understanding of biological and clinical heterogeneity. However, developmental origins of PB subgroup heterogeneity and mechanisms governing how specific genetic alterations promote malignancy remain unknown. We conducted single-nucleus RNA sequencing of 38 primary tumors, including cases from all subgroups, to uncover intra-tumoral heterogeneity, developmental origins and expose selective dependencies. Transcriptional programs driving intra-tumoral heterogeneity showed subgroup-specific patterns such as mRNA splicing associated with PB-miRNA1/2 and phototransduction in PB-RB and PB-MYC/FOXR2. Next, we created a single-cell transcriptional atlas of the murine pineal gland across 11 developmental stages and found significant associations between PB subgroups and specific differentiation states of the pinealocyte lineage, suggesting subgroup-specific developmental origins. Characterization of pineal development informed generation of biologically faithful disease models, including a novel genetically engineered mouse model of the PB-RB subgroup. PB-Rb1 mouse tumors were histologically and molecularly validated for their fidelity to human tumor counterparts, exhibiting up-regulation of key pinealocyte lineage markers that are diagnostic in patients. Using cell lines derived from our PB-Rb1 mouse model we identified several transcription factor dependencies we believe are high-jacked during normal pinealocyte development. Our findings inform the developmental origins of pineoblastoma as well as provides candidates for potential therapeutic targets. Oxford University Press 2023-06-12 /pmc/articles/PMC10260074/ http://dx.doi.org/10.1093/neuonc/noad073.008 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Final Category: ATRT/Embryonal/ETMR - ATRT Gudenas, Brian Englinger, Bernhard Liu, Anthony P Y Ahmad, Sheikh Tanveer Meredith, David Pfaff, Elke Paul, Leena Hadley, Jennifer Batts, Melissa Klimo Jr., Paul Boop, Frederick A Gajjar, Amar Robinson, Giles W Orr, Brent A Lin, Hong Alexandrescu, Sanda Jones, David T W Filbin, Mariella G Northcott, Paul A ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES |
title | ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES |
title_full | ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES |
title_fullStr | ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES |
title_full_unstemmed | ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES |
title_short | ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES |
title_sort | atrt-08. the single-cell landscape of pineoblastoma identifies developmental origins and exposes tumorigenic dependencies |
topic | Final Category: ATRT/Embryonal/ETMR - ATRT |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260074/ http://dx.doi.org/10.1093/neuonc/noad073.008 |
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