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  1. Article ; Online: DeepVelo: deep learning extends RNA velocity to multi-lineage systems with cell-specific kinetics.

    Cui, Haotian / Maan, Hassaan / Vladoiu, Maria C / Zhang, Jiao / Taylor, Michael D / Wang, Bo

    Genome biology

    2024  Volume 25, Issue 1, Page(s) 27

    Abstract: Existing RNA velocity estimation methods strongly rely on predefined dynamics and cell-agnostic constant transcriptional kinetic rates, assumptions often violated in complex and heterogeneous single-cell RNA sequencing (scRNA-seq) data. Using a graph ... ...

    Abstract Existing RNA velocity estimation methods strongly rely on predefined dynamics and cell-agnostic constant transcriptional kinetic rates, assumptions often violated in complex and heterogeneous single-cell RNA sequencing (scRNA-seq) data. Using a graph convolution network, DeepVelo overcomes these limitations by generalizing RNA velocity to cell populations containing time-dependent kinetics and multiple lineages. DeepVelo infers time-varying cellular rates of transcription, splicing, and degradation, recovers each cell's stage in the differentiation process, and detects functionally relevant driver genes regulating these processes. Application to various developmental and pathogenic processes demonstrates DeepVelo's capacity to study complex differentiation and lineage decision events in heterogeneous scRNA-seq data.
    MeSH term(s) Gene Expression Profiling/methods ; Sequence Analysis, RNA/methods ; Deep Learning ; RNA/genetics ; Cell Differentiation/genetics ; Single-Cell Analysis/methods
    Chemical Substances RNA (63231-63-0)
    Language English
    Publishing date 2024-01-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-023-03148-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Intracellular galectins in cancer cells: potential new targets for therapy (Review).

    Vladoiu, Maria C / Labrie, Marilyne / St-Pierre, Yves

    International journal of oncology

    2014  Volume 44, Issue 4, Page(s) 1001–1014

    Abstract: Dysregulation of galectin expression is frequently observed in cancer tissues. Such an abnormal expression pattern often correlates with aggressiveness and relapse in many types of cancer. Because galectins have the ability to modulate functions that are ...

    Abstract Dysregulation of galectin expression is frequently observed in cancer tissues. Such an abnormal expression pattern often correlates with aggressiveness and relapse in many types of cancer. Because galectins have the ability to modulate functions that are important for cell survival, migration and metastasis, they also represent attractive targets for cancer therapy. This has been well-exploited for extracellular galectins, which bind glycoconjugates expressed on the surface of cancer cells. Although the existence of intracellular functions of galectins has been known for many years, an increasing number of studies indicate that these proteins can also alter tumor progression through their interaction with intracellular ligands. In fact, in some instances, the interactions of galectins with their intracellular ligands seem to occur independently of their carbohydrate recognition domain. Such findings call for a change in the basic assumptions, or paradigms, concerning the activity of galectins in cancer and may force us to revisit our strategies to develop galectin antagonists for the treatment of cancer.
    MeSH term(s) Apoptosis/physiology ; Cell Adhesion/physiology ; Cell Proliferation ; Cell Transformation, Neoplastic/pathology ; Galectins/antagonists & inhibitors ; Galectins/biosynthesis ; Galectins/metabolism ; Humans ; Neoplasm Invasiveness/pathology ; Neoplasm Metastasis/pathology ; Neoplasms/immunology ; Neoplasms/pathology ; Neovascularization, Pathologic/pathology ; Protein Binding ; Tumor Escape/immunology
    Chemical Substances Galectins
    Language English
    Publishing date 2014-04
    Publishing country Greece
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1154403-x
    ISSN 1791-2423 ; 1019-6439
    ISSN (online) 1791-2423
    ISSN 1019-6439
    DOI 10.3892/ijo.2014.2267
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Developmental basis of SHH medulloblastoma heterogeneity.

    Gold, Maxwell P / Ong, Winnie / Masteller, Andrew M / Ghasemi, David R / Galindo, Julie Anne / Park, Noel R / Huynh, Nhan C / Donde, Aneesh / Pister, Veronika / Saurez, Raul A / Vladoiu, Maria C / Hwang, Grace H / Eisemann, Tanja / Donovan, Laura K / Walker, Adam D / Benetatos, Joseph / Dufour, Christelle / Garzia, Livia / Segal, Rosalind A /
    Wechsler-Reya, Robert J / Mesirov, Jill P / Korshunov, Andrey / Pajtler, Kristian W / Pomeroy, Scott L / Ayrault, Olivier / Davidson, Shawn M / Cotter, Jennifer A / Taylor, Michael D / Fraenkel, Ernest

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 270

    Abstract: Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) ... ...

    Abstract Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.
    MeSH term(s) Humans ; Hedgehog Proteins/genetics ; Medulloblastoma/genetics ; Proteomics ; Cerebellum ; Cerebellar Neoplasms/genetics
    Chemical Substances Hedgehog Proteins ; SHH protein, human
    Language English
    Publishing date 2024-01-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-44300-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours.

    Hamed, Akram A / Kunz, Daniel J / El-Hamamy, Ibrahim / Trinh, Quang M / Subedar, Omar D / Richards, Laura M / Foltz, Warren / Bullivant, Garrett / Ware, Matthaeus / Vladoiu, Maria C / Zhang, Jiao / Raj, Antony M / Pugh, Trevor J / Taylor, Michael D / Teichmann, Sarah A / Stein, Lincoln D / Simons, Benjamin D / Dirks, Peter B

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 4178

    Abstract: Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from ... ...

    Abstract Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and paediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that prenatal transformation of RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.
    MeSH term(s) Animals ; Brain ; Cerebrum ; Child ; Glioma/genetics ; Humans ; Mice ; Neurogenesis ; Telencephalon
    Language English
    Publishing date 2022-07-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-31408-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2

    Selvadurai, Hayden J / Luis, Erika / Desai, Kinjal / Lan, Xiaoyang / Vladoiu, Maria C / Whitley, Owen / Galvin, Ciaran / Vanner, Robert J / Lee, Lilian / Whetstone, Heather / Kushida, Michelle / Nowakowski, Tomasz / Diamandis, Phedias / Hawkins, Cynthia / Bader, Gary / Kriegstein, Arnold / Taylor, Michael D / Dirks, Peter B

    Cell reports

    2020  Volume 31, Issue 2, Page(s) 107511

    Abstract: Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with ... ...

    Abstract Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2
    MeSH term(s) Animals ; Cell Lineage/genetics ; Cells, Cultured ; Cerebellar Neoplasms/pathology ; Cerebellum/embryology ; Female ; Hedgehog Proteins/metabolism ; Humans ; Male ; Medulloblastoma/etiology ; Medulloblastoma/metabolism ; Mice, Knockout ; Mice, Transgenic ; Neoplasm Recurrence, Local/pathology ; Neural Stem Cells/metabolism ; Neurogenesis ; Neurons/metabolism ; SOXB1 Transcription Factors/metabolism ; SOXB1 Transcription Factors/physiology ; Signal Transduction/physiology ; Single-Cell Analysis/methods
    Chemical Substances Hedgehog Proteins ; SOX2 protein, human ; SOXB1 Transcription Factors
    Language English
    Publishing date 2020-04-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2020.03.075
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate.

    Zagozewski, Jamie / Shahriary, Ghazaleh M / Morrison, Ludivine Coudière / Saulnier, Olivier / Stromecki, Margaret / Fresnoza, Agnes / Palidwor, Gareth / Porter, Christopher J / Forget, Antoine / Ayrault, Olivier / Hawkins, Cynthia / Chan, Jennifer A / Vladoiu, Maria C / Sundaresan, Lakshmikirupa / Arsenio, Janilyn / Taylor, Michael D / Ramaswamy, Vijay / Werbowetski-Ogilvie, Tamra E

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 3627

    Abstract: OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 ... ...

    Abstract OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis.
    MeSH term(s) Animals ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Cell Differentiation/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Cerebellar Neoplasms/genetics ; Cerebellar Neoplasms/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Medulloblastoma/genetics ; Medulloblastoma/metabolism ; Neoplastic Stem Cells/metabolism ; Oncogenes ; Otx Transcription Factors/metabolism ; PAX3 Transcription Factor/genetics ; PAX3 Transcription Factor/metabolism ; PAX6 Transcription Factor/genetics ; PAX6 Transcription Factor/metabolism ; Signal Transduction/genetics
    Chemical Substances OTX2 protein, human ; Otx Transcription Factors ; PAX3 Transcription Factor ; PAX3 protein, human ; PAX6 Transcription Factor ; PAX6 protein, human
    Language English
    Publishing date 2020-07-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-17357-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas.

    Jessa, Selin / Mohammadnia, Abdulshakour / Harutyunyan, Ashot S / Hulswit, Maud / Varadharajan, Srinidhi / Lakkis, Hussein / Kabir, Nisha / Bashardanesh, Zahedeh / Hébert, Steven / Faury, Damien / Vladoiu, Maria C / Worme, Samantha / Coutelier, Marie / Krug, Brian / Faria Andrade, Augusto / Pathania, Manav / Bajic, Andrea / Weil, Alexander G / Ellezam, Benjamin /
    Atkinson, Jeffrey / Dudley, Roy W R / Farmer, Jean-Pierre / Perreault, Sebastien / Garcia, Benjamin A / Larouche, Valérie / Blanchette, Mathieu / Garzia, Livia / Bhaduri, Aparna / Ligon, Keith L / Bandopadhayay, Pratiti / Taylor, Michael D / Mack, Stephen C / Jabado, Nada / Kleinman, Claudia L

    Nature genetics

    2022  Volume 54, Issue 12, Page(s) 1865–1880

    Abstract: Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple ...

    Abstract Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations and molecular profiles. The contribution of the cell of origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte precursor cells (OPCs). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1
    MeSH term(s) Cell Lineage/genetics ; Epigenomics ; Chromatin ; Brain
    Chemical Substances Chromatin
    Language English
    Publishing date 2022-12-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-022-01205-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Author Correction: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

    Donovan, Laura K / Delaidelli, Alberto / Joseph, Sujith K / Bielamowicz, Kevin / Fousek, Kristen / Holgado, Borja L / Manno, Alex / Srikanthan, Dilakshan / Gad, Ahmed Z / Van Ommeren, Randy / Przelicki, David / Richman, Cory / Ramaswamy, Vijay / Daniels, Craig / Pallota, Jonelle G / Douglas, Tajana / Joynt, Alyssa C M / Haapasalo, Joonas / Nor, Carolina /
    Vladoiu, Maria C / Kuzan-Fischer, Claudia M / Garzia, Livia / Mack, Stephen C / Varadharajan, Srinidhi / Baker, Matthew L / Hendrikse, Liam / Ly, Michelle / Kharas, Kaitlin / Balin, Polina / Wu, Xiaochong / Qin, Lei / Huang, Ning / Stucklin, Ana Guerreiro / Morrissy, A Sorana / Cavalli, Florence M G / Luu, Betty / Suarez, Raul / De Antonellis, Pasqualino / Michealraj, Antony / Rastan, Avesta / Hegde, Meenakshi / Komosa, Martin / Sirbu, Olga / Kumar, Sachin A / Abdullaev, Zied / Faria, Claudia C / Yip, Stephen / Hukin, Juliette / Tabori, Uri / Hawkins, Cynthia / Aldape, Ken / Daugaard, Mads / Maris, John M / Sorensen, Poul H / Ahmed, Nabil / Taylor, Michael D

    Nature medicine

    2021  Volume 27, Issue 6, Page(s) 1117–1120

    Language English
    Publishing date 2021-06-14
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-021-01362-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse.

    Zhang, Liguo / He, Xuelian / Liu, Xuezhao / Zhang, Feng / Huang, L Frank / Potter, Andrew S / Xu, Lingli / Zhou, Wenhao / Zheng, Tao / Luo, Zaili / Berry, Kalen P / Pribnow, Allison / Smith, Stephanie M / Fuller, Christine / Jones, Blaise V / Fouladi, Maryam / Drissi, Rachid / Yang, Zeng-Jie / Gustafson, W Clay /
    Remke, Marc / Pomeroy, Scott L / Girard, Emily J / Olson, James M / Morrissy, A Sorana / Vladoiu, Maria C / Zhang, Jiao / Tian, Weidong / Xin, Mei / Taylor, Michael D / Potter, S Steven / Roussel, Martine F / Weiss, William A / Lu, Q Richard

    Cancer cell

    2019  Volume 36, Issue 3, Page(s) 302–318.e7

    Abstract: Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) ... ...

    Abstract Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2
    MeSH term(s) Animals ; Brain Neoplasms ; Cell Line, Tumor ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Child, Preschool ; Datasets as Topic ; Disease Models, Animal ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Gene Regulatory Networks ; Hedgehog Proteins/metabolism ; Humans ; Male ; Medulloblastoma/genetics ; Medulloblastoma/mortality ; Medulloblastoma/pathology ; Mice, Transgenic ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Neoplastic Stem Cells/pathology ; Neuroglia/pathology ; Oligodendrocyte Transcription Factor 2/genetics ; Oligodendrocyte Transcription Factor 2/metabolism ; Prognosis ; RNA-Seq ; Signal Transduction/genetics ; Single-Cell Analysis ; Survival Analysis ; Transcriptome
    Chemical Substances Hedgehog Proteins ; OLIG2 protein, human ; Olig2 protein, mouse ; Oligodendrocyte Transcription Factor 2
    Language English
    Publishing date 2019-08-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2019.07.009
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  10. Article ; Online: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

    Donovan, Laura K / Delaidelli, Alberto / Joseph, Sujith K / Bielamowicz, Kevin / Fousek, Kristen / Holgado, Borja L / Manno, Alex / Srikanthan, Dilakshan / Gad, Ahmed Z / Van Ommeren, Randy / Przelicki, David / Richman, Cory / Ramaswamy, Vijay / Daniels, Craig / Pallota, Jonelle G / Douglas, Tajana / Joynt, Alyssa C M / Haapasalo, Joonas / Nor, Carolina /
    Vladoiu, Maria C / Kuzan-Fischer, Claudia M / Garzia, Livia / Mack, Stephen C / Varadharajan, Srinidhi / Baker, Matthew L / Hendrikse, Liam / Ly, Michelle / Kharas, Kaitlin / Balin, Polina / Wu, Xiaochong / Qin, Lei / Huang, Ning / Stucklin, Ana Guerreiro / Morrissy, A Sorana / Cavalli, Florence M G / Luu, Betty / Suarez, Raul / De Antonellis, Pasqualino / Michealraj, Antony / Rastan, Avesta / Hegde, Meenakshi / Komosa, Martin / Sirbu, Olga / Kumar, Sachin A / Abdullaev, Zied / Faria, Claudia C / Yip, Stephen / Hukin, Juliette / Tabori, Uri / Hawkins, Cynthia / Aldape, Ken / Daugaard, Mads / Maris, John M / Sorensen, Poul H / Ahmed, Nabil / Taylor, Michael D

    Nature medicine

    2020  Volume 26, Issue 5, Page(s) 720–731

    Abstract: Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located ... ...

    Abstract Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.
    MeSH term(s) Animals ; Brain Neoplasms/cerebrospinal fluid ; Brain Neoplasms/immunology ; Brain Neoplasms/pathology ; Brain Neoplasms/therapy ; Cancer Vaccines/administration & dosage ; Cerebellar Neoplasms/cerebrospinal fluid ; Cerebellar Neoplasms/immunology ; Cerebellar Neoplasms/pathology ; Cerebellar Neoplasms/therapy ; Cerebrospinal Fluid/drug effects ; Cerebrospinal Fluid/immunology ; Child ; Child, Preschool ; Drug Delivery Systems/methods ; Ependymoma/cerebrospinal fluid ; Ependymoma/immunology ; Ependymoma/pathology ; Ependymoma/therapy ; Female ; HEK293 Cells ; Humans ; Immunotherapy, Adoptive/methods ; Infant ; Injections, Intraventricular ; Male ; Medulloblastoma/cerebrospinal fluid ; Medulloblastoma/immunology ; Medulloblastoma/pathology ; Medulloblastoma/therapy ; Mice ; Neoplasm Metastasis ; Receptors, Chimeric Antigen/administration & dosage ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation ; Treatment Outcome ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances Cancer Vaccines ; Receptors, Chimeric Antigen
    Language English
    Publishing date 2020-04-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Validation Study
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-020-0827-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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