Morag Park

McGill University, Montréal, Quebec, Canada

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Publications (107)839.32 Total impact

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    ABSTRACT: When expressed alone at high levels, the human adenovirus E4orf4 protein exhibits tumor cell-specific p53-independent toxicity. A major E4orf4 target is the B55 class of PP2A regulatory subunits and we have shown recently that binding of E4orf4 inhibits PP2A(B55) phosphatase activity in a dose-dependent fashion by preventing access of substrates. While interaction with B55 subunits is essential for toxicity, E4orf4 mutants exist that, despite binding B55 at high levels, are defective in cell killing, suggesting that other essential targets may exist. In an attempt to identify additional targets we undertook a proteomics approach to characterize E4orf4-interacting proteins. Our findings indicated that, in addition to PP2A(B55) subunits, ASPP-PP1 complex subunits were found among the major E4orf4-binding species. Both the PP2A and ASPP-PP1 phosphatases are known to positively regulate effectors of the Hippo signaling pathway that controls expression of cell growth/survival genes by dephosphorylating the YAP transcriptional co-activator. We find here that expression of E4orf4 results in hyperphosphorylation of YAP, suggesting that Hippo signaling may be affected by E4orf4 interactions with PP2A(B55) and/or ASPP-PP1 phosphatases. Furthermore, knockdown YAP1 expression was seen to enhance E4orf4 killing, again consistent with a link between E4orf4 toxicity and inhibition of the Hippo pathway. This effect may in fact contribute to the cancer cell specificity of E4orf4 toxicity as many human cancer cells rely heavily on the Hippo pathway for their enhanced proliferation. The human adenovirus E4orf4 protein has been known for some time to induce tumor cell-specific death when expressed at high levels, and thus knowledge of its mode of action could be of importance for development of new cancer therapies. Although the B55 form of the phosphatase PP2A has long been known as an essential E4orf4 target, genetic analyses indicated that others must exist. To identify additional E4orf4 targets we performed, for the first time, a large scale affinity purification/mass spectrometry analysis of E4orf4 binding partners. Several additional candidates were detected, including key regulators of the Hippo signaling pathway that enhances cell viability in many cancers, and results of preliminary studies suggested a possible link between inhibition of Hippo signaling and E4orf4 toxicity. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 06/2015; DOI:10.1128/JVI.03710-14 · 4.65 Impact Factor
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    ABSTRACT: Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth factor (HGF) and is dysregulated in numerous human tumors. Here we show that Abl family of non-receptor tyrosine kinases, comprised of Abl (ABL1) and Arg (ABL2), are activated downstream of the Met receptor, and that inhibition of Abl kinases dramatically suppresses HGF-induced cell scattering and tubulogenesis. We uncover a critical role for Abl kinases in the regulation of HGF/Met-dependent RhoA activation and RhoA-mediated actomyosin contractility and actin cytoskeleton remodeling in epithelial cells. Moreover, treatment of breast cancer cells with Abl inhibitors markedly decreases Met-driven cell migration and invasion. Notably, expression of a transforming mutant of the Met receptor in the mouse mammary epithelium results in hyper-activation of both Abl and Arg kinases. Together these data demonstrate that Abl kinases link Met activation to Rho signaling and Abl kinases are required for Met-dependent cell scattering, tubulogenesis, migration, and invasion. Thus, inhibition of Abl kinases might be exploited for the treatment of cancers driven by hyperactivation of HGF/Met signaling.
    PLoS ONE 05/2015; 10(5):e0124960. DOI:10.1371/journal.pone.0124960 · 3.53 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P4-04-01-P4-04-01. DOI:10.1158/1538-7445.SABCS14-P4-04-01 · 9.28 Impact Factor
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    ABSTRACT: Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells.We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis.Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.
    Oncotarget 03/2015; · 6.63 Impact Factor
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    ABSTRACT: With hundreds of chromatin regulators identified in mammals, an emerging issue is how they modulate biological and pathological processes. BRPF1 (bromodomain- and PHD finger-containing protein 1) is a unique chromatin regulator possessing two PHD fingers, one bromodomain and a PWWP domain for recognizing multiple histone modifications. In addition, it binds to the acetyltransferases MOZ, MORF and HBO1 (also known as KAT6A, KAT6B and KAT7, respectively) to promote complex formation, restrict substrate specificity and enhance enzymatic activity. We have recently shown that ablation of the mouse Brpf1 gene causes embryonic lethality at E9.5. Here we present systematic analyses of the mutant animals and demonstrate that the ablation leads to vascular defects in the placenta, yolk sac and embryo proper, as well as abnormal neural tube closure. At the cellular level, Brpf1 loss inhibits proliferation of embryonic fibroblasts and primitive hematopoietic progenitors. Molecularly, the loss reduces transcription of a ribosomal protein L10 (Rpl10)-like gene and the cell cycle inhibitor p27, and increases expression of the cell-cycle inhibitor p16 and a novel protein homologous to Scp3, a synaptonemal complex protein critical for chromosome association and embryo survival. These results uncover a crucial role of Brpf1 in controlling mouse embryo development and regulating cellular and gene expression programs. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(18). DOI:10.1074/jbc.M115.643189 · 4.60 Impact Factor
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    ABSTRACT: Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.
    PLoS Genetics 03/2015; 11(3):e1005034. DOI:10.1371/journal.pgen.1005034 · 8.17 Impact Factor
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    ABSTRACT: The small guanosine triphosphatase Rab13 functions in exocytic vesicle trafficking in epithelial cells. Alterations in Rab13 activity have been observed in human cancers, yet the mechanism of Rab13 activation and its role in cancer progression remain unclear. In this paper, we identify the DENN domain protein DENND2B as the guanine nucleotide exchange factor for Rab13 and develop a novel Förster resonance energy transfer-based Rab biosensor to reveal activation of Rab13 by DENND2B at the leading edge of migrating cells. DENND2B interacts with the Rab13 effector MICAL-L2 at the cell periphery, and this interaction is required for the dynamic remodeling of the cell's leading edge. Disruption of Rab13-mediated trafficking dramatically limits the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo. Thus, blocking Rab13 activation by DENND2B may provide a novel target to limit the spread of epithelial cancers. © 2015 Ioannou et al.
    The Journal of Cell Biology 02/2015; 208(5). DOI:10.1083/jcb.201407068 · 9.69 Impact Factor
  • Cancer Research 01/2015; 75(1 Supplement):A79-A79. DOI:10.1158/1538-7445.CHTME14-A79 · 9.28 Impact Factor
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    ABSTRACT: Epigenetic mechanisms are important in different neurological disorders and one such mechanism is histone acetylation. The multivalent chromatin regulator BRPF1 (bromodomain- and PHD finger-containing protein 1) recognizes different epigenetic marks and activates three histone acetyltransferases, so it is both a reader and a co-writer of the epigenetic language. The three histone acetyltransferases are MOZ, MORF and HBO1, which are also known as lysine acetyltransferase 6A (KAT6A), KAT6B and KAT7, respectively. The MORF gene is mutated in four neurodevelopmental disorders sharing the characteristic of intellectual disability and frequently displaying callosal agenesis. Here we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities and partial callosal agenesis. With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis. Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development. Surprisingly, elevated expression of different Hox genes and various other transcription factors, such as Lhx4, Foxa1, Tbx5 and Twist1, was also observed. These results thus identify an important role of Brpf1 in regulating forebrain development and suggest that it acts as both an activator and a silencer of gene expression in vivo.
    Journal of Biological Chemistry 01/2015; 290(11). DOI:10.1074/jbc.M114.635250 · 4.60 Impact Factor
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    ABSTRACT: Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer.
    Genome biology 01/2015; 16(1):128. DOI:10.1186/s13059-015-0675-4 · 10.47 Impact Factor
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    ABSTRACT: IntroductionThis study helps to define the implications of Breast Cancer Anti-estrogen Resistant 3 (BCAR3) in breast cancer and extends current understanding of its molecular mechanism of action. BCAR3 has been shown to promote cell proliferation, migration and attachment to extracellular matrix components. However, in a cohort of metastatic breast cancer patients who received Tamoxifen treatment, high BCAR3 mRNA levels associate with favorable progression free survival outcome. These results suggest that, besides the established roles, BCAR3 may have additional mechanisms of action that regulates breast cancer aggressive phenotype. In this study, we investigate whether BCAR3 is a novel antagonist of the canonical Transforming Growth Factor beta (TGFß) pathway, which induces potent migration and invasion responses in breast cancer cells.Methods We surveyed functional genomics databases for correlations between BCAR3 expression and disease outcomes of breast cancer patients. We also studied how BCAR3 could regulate the TGFß/Smad signaling axis using Western blot, co-immunoprecipitation and luciferase assays. In addition, we examined whether BCAR3 could modulate TGFß-induced cell migration and invasion, using an automatic life content imaging system and a confocal microscopy imaging-based matrix degradation assay, respectively.ResultsRelatively low levels of BCAR3 expression in primary breast tumors correlates with distant metastasis free survival (DMFS) and relapse free survival (RFS) poor outcomes. We also found a strong correlation between the loss of heterozygosity at BCAR3 gene alleles and lymph node invasion in human breast cancer, further suggesting a role for BCAR3 in preventing disease progression. In addition, we found BCAR3 to inhibit Smad activation, Smad-mediated gene transcription, Smad-dependent cell migration and matrix digestion in breast cancer cells. Furthermore, we found BCAR3 to be down-regulated by TGFß through proteasome degradation, defining a novel positive feedback loop mechanism downstream of the TGFß/Smad signaling pathway.ConclusionBCAR3 is considered to be associated with aggressive breast cancer phenotypes. However, our results indicate that BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the pro-metastatic TGFß/Smad signaling pathway in invasive breast tumors. These data provide new insights into BCAR3¿s molecular mechanism of action and highlight BCAR3 as a novel TGFß/Smad antagonist in breast cancer.
    Breast cancer research: BCR 12/2014; 16(6):476. DOI:10.1186/s13058-014-0476-9 · 5.88 Impact Factor
  • Serhiy Havrylov, Morag Park
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    ABSTRACT: Acquired capacity of cancer cells to penetrate through the extracellular matrix (ECM) of surrounding tissues is a prerequisite for tumour metastatic spread - the main source of cancer-associated mortality. Through combined efforts of many research groups we are beginning to understand that the ability of cells to invade through the ECM is a multifaceted phenomenon supported by variety of specialised protrusive cellular structures, primarily pseudopodia, invadopodia and podosomes. Additionally, secreted extracellular vesicles (EVs) are being increasingly recognised as important mediators of invasive cell phenotypes and therefore may be considered bona fide invasive cell structures. Dissection of the molecular makings underlying biogenesis and function of all of these structures is crucial to identify novel targets for specific anti-metastatic therapies. Rapid advances and growing accessibility of MS/MS-based protein identification made this family of techniques a suitable and appropriate choice for proteomic profiling of invasive cell structures. In this review we provide a summary of current progress in the characterisation of protein composition and topology of protein interaction networks of pseudopodia, invadopodia, podosomes and EVs, as well as outline challenges and perspectives of the field. This article is protected by copyright. All rights reserved.
    Proteomics 10/2014; 15(2-3). DOI:10.1002/pmic.201400220 · 3.97 Impact Factor
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    ABSTRACT: Breast carcinoma (BC) has been extensively profiled by high-throughput technologies for over a decade, and broadly speaking, these studies can be grouped into those that seek to identify patient subtypes (studies of heterogeneity) or those that seek to identify gene signatures with prognostic or predictive capacity. The sheer number of reported signatures has led to speculation that everything is prognostic in BC. Here, we show that this ubiquity is an apparition caused by a poor understanding of the interrelatedness between subtype and the molecular determinants of prognosis. Our approach constructively shows how to avoid confounding due to a patient's subtype, clinicopathological profile, or treatment profile. The approach identifies patients who are predicted to have good outcome at time of diagnosis by all available clinical and molecular markers but who experience a distant metastasis within 5 years. These inherently difficult patients (∼7% of BC) are prioritized for investigations of intratumoral heterogeneity.
    Cell Reports 10/2014; 9(1). DOI:10.1016/j.celrep.2014.08.073 · 7.21 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):LB-77-LB-77. DOI:10.1158/1538-7445.AM2014-LB-77 · 9.28 Impact Factor
  • Emily S. Bell, Dongmei Zuo, Morag Park
    Cancer Research 10/2014; 74(19 Supplement):3453-3453. DOI:10.1158/1538-7445.AM2014-3453 · 9.28 Impact Factor
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    ABSTRACT: Autocrine activation of the Wnt/β-catenin pathway occurs in several cancers, notably in breast tumors, and is associated with higher expression of various Wnt ligands. Using various inhibitors of the FZD/LRP receptor complex, we demonstrate that some adenosquamous carcinomas that develop in MMTV-CUX1 transgenic mice represent a model for autocrine activation of the Wnt/β-catenin pathway. By comparing expression profiles of laser-capture microdissected mammary tumors, we identify Glis1 as a transcription factor that is highly expressed in the subset of tumors with elevated Wnt gene expression. Analysis of human cancer datasets confirms that elevated WNT gene expression is associated with high levels of CUX1 and GLIS1 and correlates with genes of the epithelial-to-mesenchymal transition (EMT) signature: VIM, SNAI1 and TWIST1 are elevated whereas CDH1 and OCLN are decreased. Co-expression experiments demonstrate that CUX1 and GLIS1 cooperate to stimulate TCF/β-catenin transcriptional activity and to enhance cell migration and invasion. Altogether, these results provide additional evidence for the role of GLIS1 in reprogramming gene expression and suggest a hierarchical model for transcriptional regulation of the Wnt/β-catenin pathway and the epithelial-to-mesenchymal transition.
    09/2014; 3(10). DOI:10.1242/bio.20148193
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    ABSTRACT: Breast cancers are stratified into distinct subtypes, which influence therapeutic responsiveness and patient outcome. Patients with luminal breast cancers are often associated with a better prognosis relative to other subtypes. However, subsets of patients with luminal disease remain at increased risk of cancer-related death. A critical process that increases the malignant potential of breast cancers is the epithelial-to-mesenchymal transition (EMT). The p66ShcA adaptor protein stimulates the formation of reactive oxygen species in response to stress stimuli. In this study, we report a novel role for p66ShcA in inducing an EMT in HER2+ luminal breast cancers. p66ShcA increases the migratory properties of breast cancer cells and enhances signaling downstream of the Met receptor tyrosine kinase in these tumors. Moreover, Met activation is required for a p66ShcA-induced EMT in luminal breast cancer cells. Finally, elevated p66ShcA levels are associated with the acquisition of an EMT in primary breast cancers
    Molecular and Cellular Biology 09/2014; 34(19). DOI:10.1128/MCB.00341-14 · 5.04 Impact Factor
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    ABSTRACT: The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial-mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors.
    Science Signaling 04/2014; 7(322):ra38. DOI:10.1126/scisignal.2004839 · 7.65 Impact Factor
  • Molecular Cancer Research 10/2013; 11(10 Supplement):PR01-PR01. DOI:10.1158/1557-3125.ADVBC-PR01 · 4.50 Impact Factor
  • Molecular Cancer Research 10/2013; 11(10 Supplement):B009-B009. DOI:10.1158/1557-3125.ADVBC-B009 · 4.50 Impact Factor

Publication Stats

4k Citations
839.32 Total Impact Points

Institutions

  • 1996–2015
    • McGill University
      • • Department of Biochemistry
      • • McGill Centre for Bioinformatics
      • • Department of Medicine
      Montréal, Quebec, Canada
  • 2012
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 2009
    • Université de Montréal
      Montréal, Quebec, Canada
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 2001–2006
    • McGill University Health Centre
      • Department of Oncology
      Montréal, Quebec, Canada