Zhen Zhao

Weill Cornell Medical College, New York, New York, United States

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Publications (7)40.56 Total impact

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    ABSTRACT: Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human data set analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer Cell 01/2015; 27(2). DOI:10.1016/j.ccell.2014.11.017 · 23.89 Impact Factor
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    ABSTRACT: Convincing epidemiological data suggest an inverse association between cancer and neurodegeneration, including Alzheimer's disease (AD). Since both AD and cancer are characterized by abnormal, but opposing cellular behavior, i.e., increased cell death in AD while excessive cell growth occurs in cancer, this motivates us to initiate the study into unraveling the shared genes and cell signaling pathways linking AD and glioblastoma multiform (GBM). In this study, a comprehensive bioinformatics analysis on clinical microarray datasets of 1,091 GBM and 524 AD cohorts was performed. Significant genes and pathways were identified from the bioinformatics analyses - in particular ERK/MAPK signaling, up-regulated in GBM and Angiopoietin Signaling pathway, reciprocally up-regulated in AD - connecting GBM and AD (P < 0.001), were investigated in details for their roles in GBM growth in an AD environment. Our results showed that suppression of GBM growth in an AD background was mediated by the ERK-AKT-p21-cell cycle pathway and anti-angiogenesis pathway.
    Scientific Reports 12/2013; 3:3467. DOI:10.1038/srep03467 · 5.08 Impact Factor
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    ABSTRACT: Decreased cerebral blood flow causes brain ischemia and plays an important role in the pathophysiology of many neurodegenerative diseases, including Alzheimer's disease and vascular dementia. In this study, we photomodulated astrocytes in the live animal by a combination of two-photon calcium uncaging in the astrocyte endfoot and in vivo imaging of neurovasculature and astrocytes by intravital two-photon microscopy after labeling with cell type specific fluorescent dyes. Our study demonstrates that photomodulation at the endfoot of a single astrocyte led to a 25% increase in the diameter of a neighboring arteriole, which is a crucial factor regulating cerebral microcirculation in downstream capillaries. Two-photon uncaging in the astrocyte soma or endfoot near veins does not show the same effect on microcirculation. These experimental results suggest that infrared photomodulation on astrocyte endfeet may be a strategy to increase cerebral local microcirculation and thus prevent brain ischemia.
    Journal of Biomedical Optics 12/2013; 18(12):126012. DOI:10.1117/1.JBO.18.12.126012 · 2.75 Impact Factor
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    ABSTRACT: Neurovascular dysfunction in many neurodegenerative diseases, such as Alzheimer’s disease (AD), reduces blood flow to affected brain areas and causes neuronal dysfunction and loss. A new optical imaging technique is developed to activate astrocytes in live animal models in order to investigate the increase of local cerebral blood flow as a potential therapeutic strategy for AD. The technique uses fluorescent labeling of vasculature and astrocytes coupled with intravital 2-photon microscopy to visualize the astrocyte-vasculature interactions in live animals. Using femtosecond laser stimulation, calcium uncaging is applied to specifically target and activate astrocytes in vivo with high spatial and temporal resolutions. Intravital 2-photon microscopy imaging was employed to demonstrate that single endfoot optical activation around an arteriole induced a 25% increase in arteriole diameter, which in turn increased cerebral local blood flow in down-stream capillaries. This quantitative result indicates the potential of using optical activation of astrocytes in afflicted brain areas of neurodegeneration to restore normal neurovascular functions.
    Conference on Photonic Therapeutics and Diagnostics IX; 03/2013
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    ABSTRACT: Deep brain stimulation (DBS) of the cholinergic nuclei has emerged as a powerful potential treatment for neurodegenerative disease and is currently in a clinical trial for Alzheimer’s therapy. While effective in treatment for a number of conditions from depression to epilepsy, DBS remains somewhat unpredictable due to the heterogeneity of the projection neurons that are activated, including glutamatergic, GABAergic, and cholinergic neurons, leading to unacceptable side effects ranging from apathy to depression or even suicidal behavior. It would be highly advantageous to confine stimulation to specific populations of neurons, particularly in brain diseases involving complex network interactions such as Alzheimer’s. Optogenetics, now firmly established as an effective approach to render genetically-defined populations of cells sensitive to light activation including mice expressing Channelrhodopsin-2 specifically in cholinergic neurons, provides just this opportunity. Here we characterize the light activation properties and cell density of cholinergic neurons in healthy mice and mouse models of Alzheimer’s disease in order to evaluate the feasibility of using optogenetic modulation of cholinergic synaptic activity to slow or reverse neurodegeneration. This paper is one of the very first reports to suggest that, despite the anatomical depth of their cell bodies, cholinergic projection neurons provide a better target for systems level optogenetic modulation than cholinergic interneurons found in various brain regions including striatum and the cerebral cortex. Additionally, basal forebrain channelrhodopsin-expressing cholinergic neurons are shown to exhibit normal distribution at 60 days and normal light activation at 40 days, the latest timepoints observed. The data collected form the basis of ongoing computational modeling of light stimulation of entire populations of cholinergic neurons.
    Conference on Photonic Therapeutics and Diagnostics IX; 03/2013
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    ABSTRACT: Brain-metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear. The role of EGFR in BMBC was explored by serial analyses in a brain-trophic clone of human MDA-MB-231 breast carcinoma cells (231-BR cells). EGFR expression was inhibited by stable short-hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo. EGFR inhibition or activation strongly affected 231-BR cell migration/invasion activities as assessed by an adhesion assay, a wound-healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231-BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an anchorage-independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3-kinase/protein kinase B and phospholipase C γ downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen-activated protein kinase pathway. The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231-BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012. © 2012 American Cancer Society.
    Cancer 11/2012; 118(21):5198-209. DOI:10.1002/cncr.27553 · 4.90 Impact Factor
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    ABSTRACT: Thrombus and secondary thrombosis plays a key role in stroke. Recent molecular imaging provides in vivo imaging of activated factor XIII (FXIIIa), an important mediator of thrombosis or fibrinolytic resistance. The present study was to investigate the fibrin deposition in a thromboembolic stroke mice model by FXIIIa-targeted near-infrared fluorescence (NIRF) imaging. The experimental protocol was approved by our institutional animal use committee. Seventy-six C57B/6J mice were subjected to thromboembolic middle cerebral artery occlusion or sham operation. Mice were either intravenously injected with the FXIIIa-targeted probe or control probe. In vivo and ex vivo NIRF imaging were performed thereafter. Probe distribution was assessed with fluorescence microscopy by spectral imaging and quantification system. MR scans were performed to measure lesion volumes in vivo, which were correlated with histology after animal euthanasia. In vivo significant higher fluorescence intensity over the ischemia-affected hemisphere, compared to the contralateral side, was detected in mice that received FXIIIa-targeted probe, but not in the controlled mice. Significantly NIRF signals showed time-dependent processes from 8 to 96 hours after injection of FXIIIa-targeted probes. Ex vivo NIRF image showed an intense fluorescence within the ischemic territory only in mice injected with FXIIIa-targeted probe. The fluorescence microscopy demonstrated distribution of FXIIIa-targeted probe in the ischemic region and nearby micro-vessels, and FXIIIa-targeted probe signals showed good overlap with immune-fluorescent fibrin staining images. There was a significant correlation between total targeted signal from in vivo or ex vivo NIRF images and lesion volume. Non-invasive detection of fibrin deposition in ischemic mouse brain using NIRF imaging is feasible and this technique may provide an in vivo experimental tool in studying the role of fibrin in stroke.
    PLoS ONE 01/2012; 7(1):e30262. DOI:10.1371/journal.pone.0030262 · 3.53 Impact Factor

Publication Stats

28 Citations
40.56 Total Impact Points

Institutions

  • 2013–2015
    • Weill Cornell Medical College
      New York, New York, United States
    • Houston Methodist Hospital
      Houston, Texas, United States
  • 2012
    • Southeast University (China)
      Nan-ching-hsü, Jiangxi Sheng, China