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  1. Article ; Online: Role of extracellular vesicles in cancer-specific interactions between tumour cells and the vasculature.

    Adnani, Lata / Spinelli, Cristiana / Tawil, Nadim / Rak, Janusz

    Seminars in cancer biology

    2022  Volume 87, Page(s) 196–213

    Abstract: Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the ... ...

    Abstract Cancer progression impacts and exploits the vascular system in several highly consequential ways. Among different types of vascular cells, blood cells and mediators that are engaged in these processes, endothelial cells are at the centre of the underlying circuitry, as crucial constituents of angiogenesis, angiocrine stimulation, non-angiogenic vascular growth, interactions with the coagulation system and other responses. Tumour-vascular interactions involve soluble factors, extracellular matrix molecules, cell-cell contacts, as well as extracellular vesicles (EVs) carrying assemblies of molecular effectors. Oncogenic mutations and transforming changes in the cancer cell genome, epigenome and signalling circuitry exert important and often cancer-specific influences upon pathways of tumour-vascular interactions, including the biogenesis, content, and biological activity of EVs and responses of cancer cells to them. Notably, EVs may carry and transfer bioactive, oncogenic macromolecules (oncoproteins, RNA, DNA) between tumour and vascular cells and thereby elicit unique functional changes and forms of vascular growth and remodeling. Cancer EVs influence the state of the vasculature both locally and systemically, as exemplified by cancer-associated thrombosis. EV-mediated communication pathways represent attractive targets for therapies aiming at modulation of the tumour-vascular interface (beyond angiogenesis) and could also be exploited for diagnostic purposes in cancer.
    MeSH term(s) Humans ; Endothelial Cells ; Extracellular Vesicles/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism ; Oncogenes ; Neovascularization, Pathologic/metabolism
    Language English
    Publishing date 2022-11-10
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2022.11.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Extracellular Vesicle Mediated Vascular Pathology in Glioblastoma.

    Spinelli, Cristiana / Tawil, Nadim / Adnani, Lata / Rak, Janusz / Choi, Dongsic

    Sub-cellular biochemistry

    2021  Volume 97, Page(s) 247–273

    Abstract: Glioblastoma (GBM) is an incurable, infiltrative high-grade brain tumour associated with dramatic vascular responses observed both locally (angiogenesis, vascular cooption, angiocrine effects, microthrombosis) and systemically (venous thromboembolism). ... ...

    Abstract Glioblastoma (GBM) is an incurable, infiltrative high-grade brain tumour associated with dramatic vascular responses observed both locally (angiogenesis, vascular cooption, angiocrine effects, microthrombosis) and systemically (venous thromboembolism). GBM-associated vascular pathology is diagnostically relevant and constitutes a source of morbidity, mortality and progressive changes in tumour biology. Extracellular vesicles (EVs) have emerged as unique mediators of vascular effects in brain tumours acting as vehicles for intercellular transfer of oncoproteins (e.g. EGFRvIII), RNA, DNA and molecular effectors of angiogenesis and thrombosis. Vascular effects of GBM EVs are regulated by cancer cell genome, epigenome and microenvironment and differ between subtypes of cancer cells and stem cells. Understanding and targeting EV-driven vascular processes in GBM may offer new approaches to diagnose and treat these intractable tumours.
    MeSH term(s) Brain ; Brain Neoplasms ; Extracellular Vesicles ; Glioblastoma ; Humans ; Tumor Microenvironment
    Language English
    Publishing date 2021-03-29
    Publishing country United States
    Document type Journal Article
    ISSN 0306-0225 ; 0096-8757
    ISSN 0306-0225 ; 0096-8757
    DOI 10.1007/978-3-030-67171-6_10
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells.

    Adnani, Lata / Kassouf, Jordan / Meehan, Brian / Spinelli, Cristiana / Tawil, Nadim / Nakano, Ichiro / Rak, Janusz

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 5494

    Abstract: Glioblastoma (GBM) is an incurable form of primary astrocytic brain tumor driven by glioma stem cell (GSC) compartment closely associated with the vascular niche. GSC phenotypes are heterogeneous and range from proneural to mesenchymal-like, the latter ... ...

    Abstract Glioblastoma (GBM) is an incurable form of primary astrocytic brain tumor driven by glioma stem cell (GSC) compartment closely associated with the vascular niche. GSC phenotypes are heterogeneous and range from proneural to mesenchymal-like, the latter characterised by greater invasiveness. Here we document the secretory (angiocrine) role of endothelial cells and their derived extracellular vesicles (EVs) as drivers of proneural-to-mesenchymal reprogramming of GSCs. These changes involve activation of matrix metalloproteinases (MMPs) and NFκB, and inactivation of NOTCH, while altering responsiveness to chemotherapy and driving infiltrative growth in the brain. Our findings suggest that EV-mediated angiocrine interactions impact the nature of cellular stemness in GBM with implications for disease biology and therapy.
    MeSH term(s) Endothelial Cells/pathology ; Extracellular Vesicles/pathology ; Glioblastoma/pathology ; Glioma/pathology ; Humans ; Neoplastic Stem Cells/pathology
    Language English
    Publishing date 2022-09-19
    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/s41467-022-33235-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mesenchymal glioma stem cells trigger vasectasia-distinct neovascularization process stimulated by extracellular vesicles carrying EGFR.

    Spinelli, Cristiana / Adnani, Lata / Meehan, Brian / Montermini, Laura / Huang, Sidong / Kim, Minjun / Nishimura, Tamiko / Croul, Sidney E / Nakano, Ichiro / Riazalhosseini, Yasser / Rak, Janusz

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 2865

    Abstract: Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) ... ...

    Abstract Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) trigger distinct endothelial responses involving either angiogenic or circumferential vascular growth (vasectasia). The latter process is selectively triggered by mesenchymal (but not proneural) GSCs and is mediated by a subset of extracellular vesicles (EVs) able to transfer EGFR/EGFRvIII transcript to endothelial cells. Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs.
    MeSH term(s) Humans ; Animals ; Mice ; Endothelial Cells/metabolism ; Glioma/metabolism ; Glioblastoma/metabolism ; ErbB Receptors/metabolism ; Extracellular Vesicles/metabolism ; Neoplastic Stem Cells/metabolism ; Brain Neoplasms/metabolism
    Chemical Substances ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1)
    Language English
    Publishing date 2024-04-03
    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/s41467-024-46597-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Extracellular Vesicles as Conduits of Non-Coding RNA Emission and Intercellular Transfer in Brain Tumors.

    Spinelli, Cristiana / Adnani, Lata / Choi, Dongsic / Rak, Janusz

    Non-coding RNA

    2018  Volume 5, Issue 1

    Abstract: Non-coding RNA (ncRNA) species have emerged in as molecular fingerprints and regulators of brain tumor pathogenesis and progression. While changes in ncRNA levels have been traditionally regarded as cell intrinsic there is mounting evidence for their ... ...

    Abstract Non-coding RNA (ncRNA) species have emerged in as molecular fingerprints and regulators of brain tumor pathogenesis and progression. While changes in ncRNA levels have been traditionally regarded as cell intrinsic there is mounting evidence for their extracellular and paracrine function. One of the key mechanisms that enables ncRNA to exit from cells is their selective packaging into extracellular vesicles (EVs), and trafficking in the extracellular space and biofluids. Vesicular export processes reduce intracellular levels of specific ncRNA in EV donor cells while creating a pool of EV-associated ncRNA in the extracellular space and biofluids that enables their uptake by other recipient cells; both aspects have functional consequences. Cancer cells produce several EV subtypes (exosomes, ectosomes), which differ in their ncRNA composition, properties and function. Several RNA biotypes have been identified in the cargo of brain tumor EVs, of which microRNAs are the most studied, but other species (snRNA, YRNA, tRNA, and lncRNA) are often more abundant. Of particular interest is the link between transforming oncogenes and the biogenesis, cargo, uptake and function of tumor-derived EV, including EV content of oncogenic RNA. The ncRNA repertoire of EVs isolated from cerebrospinal fluid and serum is being developed as a liquid biopsy platform in brain tumors.
    Language English
    Publishing date 2018-12-25
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2813993-8
    ISSN 2311-553X ; 2311-553X
    ISSN (online) 2311-553X
    ISSN 2311-553X
    DOI 10.3390/ncrna5010001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Embryonic Microglia Interact with Hypothalamic Radial Glia during Development and Upregulate the TAM Receptors MERTK and AXL following an Insult.

    Rosin, Jessica M / Marsters, Candace M / Malik, Faizan / Far, Rena / Adnani, Lata / Schuurmans, Carol / Pittman, Quentin J / Kurrasch, Deborah M

    Cell reports

    2021  Volume 34, Issue 1, Page(s) 108587

    Abstract: Despite a growing appreciation for microglial influences on the developing brain, the responsiveness of microglia to insults during gestation remains less well characterized, especially in the embryo when microglia themselves are still maturing. Here, we ...

    Abstract Despite a growing appreciation for microglial influences on the developing brain, the responsiveness of microglia to insults during gestation remains less well characterized, especially in the embryo when microglia themselves are still maturing. Here, we asked if fetal microglia could coordinate an innate immune response to an exogenous insult. Using time-lapse imaging, we showed that hypothalamic microglia actively surveyed their environment by near-constant "touching" of radial glia projections. However, following an insult (i.e., IUE or AAV transduction), this seemingly passive touching became more intimate and long lasting, ultimately resulting in the retraction of radial glial projections and degeneration into small pieces. Mechanistically, the TAM receptors MERTK and AXL were upregulated in microglia following the insult, and Annexin V treatment inhibited radial glia breakage and engulfment by microglia. These data demonstrate a remarkable responsiveness of embryonic microglia to insults during gestation, a critical window for neurodevelopment.
    MeSH term(s) Animals ; Brain/embryology ; Embryo, Mammalian/metabolism ; Embryonic Development ; Ependymoglial Cells/physiology ; Gene Expression Regulation, Developmental ; Hypothalamus/embryology ; Hypothalamus/physiology ; Immunity, Innate ; Mice ; Mice, Transgenic ; Microglia/physiology ; Optical Imaging/methods ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; c-Mer Tyrosine Kinase/metabolism
    Chemical Substances Proto-Oncogene Proteins ; Mertk protein, mouse (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1)
    Language English
    Publishing date 2021-04-12
    Publishing country United States
    Document type Journal Article ; 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.2020.108587
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Mechanisms of Cortical Differentiation.

    Adnani, Lata / Han, Sisu / Li, Saiqun / Mattar, Pierre / Schuurmans, Carol

    International review of cell and molecular biology

    2017  Volume 336, Page(s) 223–320

    Abstract: During fetal and postnatal development, the human brain generates 160 billion neuronal and glial cells, each with precise cellular phenotypes. To effectively manage such a complicated task, intrinsic (e.g., transcription factors) and extrinsic ( ... ...

    Abstract During fetal and postnatal development, the human brain generates 160 billion neuronal and glial cells, each with precise cellular phenotypes. To effectively manage such a complicated task, intrinsic (e.g., transcription factors) and extrinsic (environmental signals) cues cooperate to regulate the decision by neural progenitors to continue to proliferate or to differentiate. Loss- and gain-of-function studies in the mouse brain have been instrumental in identifying these cues, leading to a fairly well-developed and well-integrated model of neocortical development. This research has revealed that the neurons, astrocytes, and oligodendrocytes that populate the mature neocortex are generated sequentially from neural progenitor pools in both the dorsal (pallial) and ventral (subpallial) telencephalon. Understanding how cellular diversity is established during neocortical development is critical, as appropriate numbers of inhibitory and excitatory neurons, oligodendrocytes, and astrocytes are required for normal neural function. Indeed, an imbalance in excitatory vs inhibitory neurotransmission or alterations in glial cell number are hallmark features of neuropsychological and intellectual disorders such as schizophrenia, bipolar disorder, and autism. Moreover, these fundamental studies are beginning to pave the way for the rational design of neural cell reprogramming strategies, which are of value for the assessment of disease etiology, and for the possible development of novel cell-based therapies. We review herein our current understanding of the intrinsic cues and environmental signals that govern cell fate specification and differentiation decisions during development of neuronal and glial lineages in the murine neocortex.
    MeSH term(s) Animals ; Cell Differentiation ; Cerebral Cortex/cytology ; Cerebral Cortex/metabolism ; Humans ; Neurogenesis ; Neurons/cytology ; Neurons/metabolism
    Language English
    Publishing date 2017-09-18
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2427220-6
    ISSN 1937-6448 ; 0074-7696
    ISSN 1937-6448 ; 0074-7696
    DOI 10.1016/bs.ircmb.2017.07.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Plag1

    Adnani, Lata / Dixit, Rajiv / Chen, Xingyu / Balakrishnan, Anjali / Modi, Harshil / Touahri, Yacine / Logan, Cairine / Schuurmans, Carol

    Biology open

    2018  Volume 7, Issue 11

    Abstract: ... ...

    Abstract The
    Language English
    Publishing date 2018-11-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 2632264-X
    ISSN 2046-6390
    ISSN 2046-6390
    DOI 10.1242/bio.038661
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Non-isotopic RNA In Situ Hybridization on Embryonic Sections.

    Touahri, Yacine / Adnani, Lata / Mattar, Pierre / Markham, Kathryn / Klenin, Natalia / Schuurmans, Carol

    Current protocols in neuroscience

    2015  Volume 70, Page(s) 1.22.1–1.22.25

    Abstract: This unit describes methods for non-isotopic RNA in situ hybridization on embryonic mouse sections. These methods can be used to follow the spatiotemporal dynamics of gene expression in an embryonic tissue of interest. They involve the use of labeled (e ... ...

    Abstract This unit describes methods for non-isotopic RNA in situ hybridization on embryonic mouse sections. These methods can be used to follow the spatiotemporal dynamics of gene expression in an embryonic tissue of interest. They involve the use of labeled (e.g., digoxygenin, FITC) antisense riboprobes that hybridize to a specific mRNA in the target tissue. The probes are detected using an alkaline phosphatase-conjugated antibody recognizing the label and a chromogenic substrate. This method can be used to: (1) assess the expression of a single gene within a tissue, (2) compare the expression profiles of two genes within a tissue, or (3) compare the distribution of a transcript and protein within a tissue. While this approach is not quantitative, it provides a qualitative assessment of the precise cell types where a gene is expressed, which is not easily achievable with other more quantitative methods such as quantitative PCR.
    MeSH term(s) Animals ; Embryo, Mammalian/chemistry ; Embryo, Mammalian/metabolism ; Genetic Techniques ; In Situ Hybridization ; Mice ; RNA Probes/metabolism ; Transcription, Genetic
    Chemical Substances RNA Probes
    Language English
    Publishing date 2015-01-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1934-8576
    ISSN (online) 1934-8576
    DOI 10.1002/0471142301.ns0122s70
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Plag1 and Plagl2 have overlapping and distinct functions in telencephalic development

    Lata Adnani / Rajiv Dixit / Xingyu Chen / Anjali Balakrishnan / Harshil Modi / Yacine Touahri / Cairine Logan / Carol Schuurmans

    Biology Open, Vol 7, Iss

    2018  Volume 11

    Abstract: The Plag gene family has three members; Plagl1/Zac1, which is a tumor suppressor gene, and Plag1 and Plagl2, which are proto-oncogenes. All three genes are known to be expressed in embryonic neural progenitors, and Zac1 regulates proliferation, neuronal ... ...

    Abstract The Plag gene family has three members; Plagl1/Zac1, which is a tumor suppressor gene, and Plag1 and Plagl2, which are proto-oncogenes. All three genes are known to be expressed in embryonic neural progenitors, and Zac1 regulates proliferation, neuronal differentiation and migration in the developing neocortex. Here we examined the functions of Plag1 and Plagl2 in neocortical development. We first attempted, and were unable to generate, E12.5 Plag1;Plagl2 double mutants, indicating that at least one Plag1 or Plagl2 gene copy is required for embryonic survival. We therefore focused on single mutants, revealing a telencephalic patterning defect in E12.5 Plagl2 mutants and a proliferation/differentiation defect in Plag1 mutant neocortices. Specifically, the ventral pallium, a dorsal telencephalic territory, expands into the ventral telencephalon in Plagl2 mutants. In contrast, Plag1 mutants develop normal regional territories, but neocortical progenitors proliferate less and instead produce more neurons. Finally, in gain-of-function studies, both Plag1 and Plagl2 reduce neurogenesis and increase BrdU-uptake, indicative of enhanced proliferation, but while Plagl2 effects on proliferation are more immediate, Plag1 effects are delayed. Taken together, we found that the Plag proto-oncogenes genes are essential regulators of neocortical development and although Plag1 and Plagl2 functions are similar, they do not entirely overlap. This article has an associated First Person interview with the first author of the paper.
    Keywords Plag gene family ; Zinc finger transcription factors ; Neocortical development ; Neural progenitor proliferation ; Neurogenesis ; Telencephalic patterning ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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