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  • American Association for Cancer Research (AACR)  (2)
  • 1
    Online Resource
    Online Resource
    Abstract 2084: Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2084-2084
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2084-2084
    Abstract: Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to universal therapeutic resistance. Here, we integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We found that local DNA methylation instability, or epimutation burden, was elevated in more aggressive tumors, reflected intratumoral variability, linked with transcriptional disruption, and associated with environmental stress response. We show that the activation of cell-state specific transcription factors is impacted by epimutations and that loosened epigenetic control may facilitate cellular plasticity. We validated the impact that the common environmental stressor hypoxia has on the epigenetic stability and shifts in cell states through perturbation-based in vitro experiments coupled with single-cell genomics. Our analyses support that glioma cells under stress hijack epigenetic mechanisms that regulate cell state transitions to overcome challenges posed by nutrient-poor microenvironments and therapeutic insults. We confirmed the link between cellular stress and epigenetic instability by analyzing larger cohorts of bulk longitudinally collected and spatially separated DNA methylation data. Increased DNA methylation instability was associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work provides an integrative framework to better understand glioma evolution and highlights the importance of epigenetic heterogeneity in shaping therapeutic response. Citation Format: Kevin C. Johnson, Kevin J. Anderson, Elise T. Courtois, Amit D. Gujar, Floris P. Barthel, Frederick S. Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos R. Estecio, Ming Tang, Nicholas E. Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C. De Witt Hamer, Ketan Bulsara, Michael L. Samuels, Sunit Das, Paul Robson, Roel G. Verhaak. Single-cell multimodal glioma analyses reveal epigenetic regulators of cellular plasticity and environmental stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2084.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2084
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 3147: Stereotactic image-guided epigenome profiling reveals a neural stem cell evolutionary origin of diffuse gliomas
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3147-3147
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3147-3147
    Abstract: Diffuse gliomas are malignant neoplasms originating in the parenchyma of the central nervous system whose cellular origin remains elusive. To determine the cellular and spatiotemporal origin of gliomas, we devised a three-dimensional reconstruction of tumor lineage. We used neuronavigation to acquire eight to twelve image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma, which we characterized using DNA methylation arrays. A total of 133 samples were obtained from regions with and without imaging abnormalities. Methylation profiles were analyzed to construct phyloepigenetic trees and subsequently projected on 3D image-derived tumor maps. Lineage analysis of these evolutionary trees indicated that the sampled gliomas largely evolved stochastically, suggesting that critical tumor drivers were acquired early in time. These results were further validated using 102 multi-region samples from 24 independent patients. Patristic (evolutionary) and cartesian (spatial) distances between pairs of tumor samples from the same patient demonstrated strong correlations, suggesting that this information could be used to determine trajectories of tumor evolution. Evolutionary and spatial distance metrics were combined with histologically obtained and computationally quantified cellularity and proliferation rates to model the direction and magnitude of tumor growth. In order to relate tumor lineage to brain anatomy we mapped patient imaging to a reference space (Montreal Neurological Institute, MNI). Samples mapping to regions of white matter were earlier in tumor lineage when compared to samples mapping to regions of gray matter, suggesting that white matter involvement is an early feature of tumor development. Samples early in tumor lineage were located closer to the ventricles when compared with samples late in lineage, suggesting that tumors grow outward from the ventricular lining. Finally, we used a tumor probability map constructed using imaging from over 500 unrelated patients to associate lineage to tumor probability. Results from this analysis indicated that periventricular areas of high tumor probability coincided with samples early in tumor lineage and cortical areas of low tumor probability coincided with samples late in tumor lineage. Taken together, our phylogeographic analysis of tumor development supports a neural progenitor cell-of-origin model, where neural stem cells in the subventricular zone of the lateral ventricles give rise to mature tumors. Citation Format: Floris P. Barthel, Niels Verburg, Russell Rockne, Roelant Eijgelaar, Kevin Anderson, Domenique Müller, Sergio Branciamore, Kevin C. Johnson, Pieter Wesseling, Philip C. de Witt Hamer, Roel G. Verhaak. Stereotactic image-guided epigenome profiling reveals a neural stem cell evolutionary origin of diffuse gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3147.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-3147
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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