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Morley, Samantha

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Morley

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Samantha

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Morley, Samantha
Author's Publications: search.filters.isAuthorOfPublication.1482fdea-e698-4c81-bf83-f98f6cafa573

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    Trading in your spindles for blebs: the amoeboid tumor cell phenotype in prostate cancer
    (Medknow Publications & Media Pvt Ltd, 2014) Morley, Samantha; Hager, Martin H; Pollan, Sara G; Knudsen, Beatrice; Di Vizio, Dolores; Freeman, Michael R.
    Prostate cancer (PCa) remains a principal cause of mortality in developed countries. Because no clinical interventions overcome resistance to androgen ablation therapy, management of castration resistance and metastatic disease remains largely untreatable. Metastasis is a multistep process in which tumor cells lose cell-cell contacts, egress from the primary tumor, intravasate, survive shear stress within the vasculature and extravasate into tissues to colonize ectopic sites. Tumor cells reestablish migratory behaviors employed during nonneoplastic processes such as embryonic development, leukocyte trafficking and wound healing. While mesenchymal motility is an established paradigm of dissemination, an alternate, ‘amoeboid’ phenotype is increasingly appreciated as relevant to human cancer. Here we discuss characteristics and pathways underlying the phenotype, and highlight our findings that the cytoskeletal regulator DIAPH3 governs the mesenchymal-amoeboid transition. We also describe our identification of a new class of tumor-derived microvesicles, large oncosomes, produced by amoeboid cells and with potential clinical utility in prostate and other cancers.
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    Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes
    (Nature Publishing Group, 2015) Morley, Samantha; You, Sungyong; Pollan, Sara; Choi, Jiyoung; Zhou, Bo; Hager, Martin H.; Steadman, Kenneth; Spinelli, Cristiana; Rajendran, Kavitha; Gertych, Arkadiusz; Kim, Jayoung; Adam, Rosalyn; Yang, Wei; Krishnan, Ramaswamy; Knudsen, Beatrice S.; Di Vizio, Dolores; Freeman, Michael R.
    Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors.
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    Integration of proteomic and transcriptomic profiles identifies a novel PDGF-MYC network in human smooth muscle cells
    (BioMed Central, 2014) Yang, Wei; Ramachandran, Aruna; You, Sungyong; Jeong, HyoBin; Morley, Samantha; Mulone, Michelle D; Logvinenko, Tanya; Kim, Jayoung; Hwang, Daehee; Freeman, Michael R.; Adam, Rosalyn
    Background: Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated. Results: Expression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation. Conclusions: These findings provide the first systems-level analysis of the PDGF-regulated transcriptome and proteome in normal smooth muscle cells. The analyses revealed an extensive cohort of PDGF-dependent biological processes and connected key transcriptional effectors to their regulation, significantly expanding current knowledge of PDGF-stimulated signaling cascades. These observations also implicate MYC as a novel target for pharmacological intervention in fibroproliferative expansion of smooth muscle, and potentially in cancers in which PDGFR-dependent signaling or MYC activation promote tumor progression.
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    Large oncosomes contain distinct protein cargo and represent a separate functional class of tumor-derived extracellular vesicles
    (Impact Journals LLC, 2015) Minciacchi, Valentina R.; You, Sungyong; Spinelli, Cristiana; Morley, Samantha; Zandian, Mandana; Aspuria, Paul-Joseph; Cavallini, Lorenzo; Ciardiello, Chiara; Sobreiro, Mariana Reis; Morello, Matteo; Kharmate, Geetanjali; Jang, Su Chul; Kim, Dae-Kyum; Hosseini-Beheshti, Elham; Guns, Emma Tomlinson; Gleave, Martin; Gho, Yong Song; Mathivanan, Suresh; Yang, Wei; Freeman, Michael R.; Di Vizio, Dolores
    Large oncosomes (LO) are atypically large (1-10μm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrepTM) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.
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    DIAPH3 Governs the Cellular Transition to the Amoeboid Tumour Phenotype
    (WILEY-VCH Verlag, 2012) Hager, Martin H; Morley, Samantha; Bielenberg, Diane; Gao, Sizhen; Morello, Matteo; Holcomb, Ilona N; Liu, Wennuan; Mouneimne, Ghassan; Demichelis, Francesca; Kim, Jayoung; Solomon, Keith R.; Adam, Rosalyn; Isaacs, William B; Higgs, Henry N; Vessella, Robert L; Di Vizio, Dolores; Freeman, Michael R.
    Therapies for most malignancies are generally ineffective once metastasis occurs. While tumour cells migrate through tissues using diverse strategies, the signalling networks controlling such behaviours in human tumours are poorly understood. Here we define a role for the Diaphanous-related formin-3 (DIAPH3) as a non-canonical regulator of metastasis that restrains conversion to amoeboid cell behaviour in multiple cancer types. The DIAPH3 locus is close to RB1, within a narrow consensus region of deletion on chromosome 13q in prostate, breast and hepatocellular carcinomas. DIAPH3 silencing in human carcinoma cells destabilized microtubules and induced defective endocytic trafficking, endosomal accumulation of EGFR, and hyperactivation of EGFR/MEK/ERK signalling. Silencing also evoked amoeboid properties, increased invasion and promoted metastasis in mice. In human tumours, DIAPH3 down-regulation was associated with aggressive or metastatic disease. DIAPH3-silenced cells were sensitive to MEK inhibition, but showed reduced sensitivity to EGFR inhibition. These findings have implications for understanding mechanisms of metastasis, and suggest that identifying patients with chromosomal deletions at DIAPH3 may have prognostic value.