Browsing by Subject "Cell migration"

Now showing 1 - 8 of 8
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    Cancer-associated fibroblasts influence Wnt/PCP signaling in gastric cancer cells by cytoneme-based dissemination of ROR2
    (National Academy of Science, 2023) Rogers, Sally; Zhang, Chengting; Anagnostidis, Vasilis; Liddle, Corin; Fishel, Melissa L.; Gielen, Fabrice; Scholpp, Steffen; Pediatrics, School of Medicine
    Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment influencing cancer progression. Besides shaping the extracellular matrix, these fibroblasts provide signaling factors to facilitate tumor survival and alter tumor behavior. In gastric cancer, one crucial signaling pathway influencing invasion and metastasis is the Wnt/Planar Cell Polarity (PCP) signaling. The crucial PCP ligand in this context is WNT5A, which is produced by the CAFs, and gastric cancer cells react upon this signal by enhanced polarized migration. Why gastric cancer cells respond to this signal is still unclear, as their expression level for the central WNT5A receptor, ROR2, is very low. Here, we show that CAFs display long and branched filopodia that form an extensive, complex network engulfing gastric cancer cells, such as the gastric cancer cell line AGS. CAFs have a significantly higher expression level of ROR2 than normal gastric fibroblasts and AGS cells. By high-resolution imaging, we observe a direct transfer of fluorescently tagged ROR2 from CAF to AGS cells by signaling filopodia, known as cytonemes. Surprisingly, we find that the transferred ROR2 complexes can activate Wnt/JNK signaling in AGS cells. Consistently, blockage of ROR2 function in the CAFs leads to reduced paracrine Wnt/JNK signaling, cell polarization, and migration of the receiving AGS cells. Complementary, enhanced migration via paracrine ROR2 transfer was observed in a zebrafish in vivo model. These findings demonstrate a fresh role for cytoneme-mediated signaling in the tumor microenvironment. Cytonemes convey Wnt receptors from CAFs to gastric cancer cells, allowing them to respond to Wnt/PCP signals.
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    Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer
    (Impact Journals, 2021-05-18) Matossian, Margarite D.; Hoang, Van T.; Burks, Hope E.; La, Jacqueline; Elliott, Steven; Brock, Courtney; Rusch, Douglas B.; Buechlein, Aaron; Nephew, Kenneth P.; Bhatt, Akshita; Cavanaugh, Jane E.; Flaherty, Patrick T.; Collins-Burow, Bridgette M.; Burow, Matthew E.; Medicine, School of Medicine
    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. A defining feature of TNBC is the propensity to metastasize and acquire resistance to cytotoxic agents. Mitogen activated protein kinase (MAPK) and extracellular regulated kinase (ERK) signaling pathways have integral roles in cancer development and progression. While MEK5/ERK5 signaling drives mesenchymal and migratory cell phenotypes in breast cancer, the specific mechanisms underlying these actions remain under-characterized. To elucidate the mechanisms through which MEK5 regulates the mesenchymal and migratory phenotype, we generated stably transfected constitutively active MEK5 (MEK5-ca) TNBC cells. Downstream signaling pathways and candidate targets of MEK5-ca cells were based on RNA sequencing and confirmed using qPCR and Western blot analyses. MEK5 activation drove a mesenchymal cell phenotype independent of cell proliferation effects. Transwell migration assays demonstrated MEK5 activation significantly increased breast cancer cell migration. In this study, we provide supporting evidence that MEK5 functions through FRA-1 to regulate the mesenchymal and migratory phenotype in TNBC.
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    Impact of ALCAM (CD166) on homing of hematopoietic stem and progenitor cells
    (2012-12-18) Aleksandrova, Mariya Aleksandrova; Goebl, Mark G.; Srour, Edward F.; Hurley, Thomas D., 1961-
    The potential of hematopoietic stem cells (HSC) to home and to anchor within the bone marrow (BM) microenvironment controls the ability of transplanted HSCs to establish normal hematopoiesis. Activated Leukocyte Cell Adhesion Molecule (ALCAM; also identified as CD166), which participates in homophilic interactions, is expressed on a group of osteoblasts in the hematopoietic niche capable of sustaining functional HSC in vitro. Since we could also detect ALCAM expression on HSC, we suspect that ALCAM may play a role in anchoring primitive hematopoietic cells to ALCAM expressing components of the hematopoietic niche via dimerization. We investigated the role of ALCAM on the homing abilities of hematopoietic stem and progenitor cells (HSPC) by calculating recovery frequency of Sca-1+ALCAM+ cells in an in vivo murine bone marrow transplantation model. Our data supports the notion that ALCAM promotes improved homing potential of hematopoietic Sca-1+ cells. Recovery of BM-homed Sca-1+ cells from the endosteal region was 1.8-fold higher than that of total donor cells. However, a 3.0-fold higher number of Sca-1+ALCAM+ cells homed to the endosteal region compared to total donor cells. Similarly, homed Sca-1+ALCAM+ cells were recovered from the vascular region at 2.1-fold greater frequency than total homed donor cells from that region, compared to only a 1.3-fold increase in the recovery frequency of Sca-1+ cells. In vitro quantitation of clonogenic BM-homed hematopoietic progenitors corroborate the results from the homing assay. The frequency of in vitro clonogenic progenitors was significantly higher among endosteal-homed Sca-1+ALCAM+ cells compared to other fractions of donor cells. Collectively, these data demonstrate that engrafting HSC expressing ALCAM home more efficiently to the BM and within the BM microenvironment, these cells preferentially seed the endosteal niche.
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    Integrin and microtubule crosstalk in the regulation of cellular processes
    (Springer Nature, 2018-11) LaFlamme, Susan E.; Mathew-Steiner, Shomita; Singh, Neetu; Colello-Borges, Diane; Nieves, Bethsaida; Surgery, School of Medicine
    Integrins engage components of the extracellular matrix, and in collaboration with other receptors, regulate signaling cascades that impact cell behavior in part by modulating the cell's cytoskeleton. Integrins have long been known to function together with the actin cytoskeleton to promote cell adhesion, migration, and invasion, and with the intermediate filament cytoskeleton to mediate the strong adhesion needed for the maintenance and integrity of epithelial tissues. Recent studies have shed light on the crosstalk between integrin and the microtubule cytoskeleton. Integrins promote microtubule nucleation, growth, and stabilization at the cell cortex, whereas microtubules regulate integrin activity and remodeling of adhesion sites. Integrin-dependent stabilization of microtubules at the cell cortex is critical to the establishment of apical-basal polarity required for the formation of epithelial tissues. During cell migration, integrin-dependent microtubule stabilization contributes to front-rear polarity, whereas microtubules promote the turnover of integrin-mediated adhesions. This review focuses on this interdependent relationship and its impact on cell behavior and function.
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    MiR-9 Controls Chemotactic Activity of Cord Blood CD34⁺ Cells by Repressing CXCR4 Expression
    (Korean Society for Stem Cell Research, 2018-11-30) Ha, Tae Won; Kang, Hyun Soo; Kim, Tae-Hee; Kwon, Ji Hyun; Kim, Hyun Kyu; Ryu, Aeli; Jeon, Hyeji; Han, Jaeseok; Broxmeyer, Hal E.; Hwang, Yongsung; Lee, Yun Kyung; Lee, Man Ryul; Microbiology and Immunology, School of Medicine
    Improved approaches for promoting umbilical cord blood (CB) hematopoietic stem cell (HSC) homing are clinically important to enhance engraftment of CB-HSCs. Clinical transplantation of CB-HSCs is used to treat a wide range of disorders. However, an improved understanding of HSC chemotaxis is needed for facilitation of the engraftment process. We found that ectopic overexpression of miR-9 and antisense-miR-9 respectively down- and up-regulated C-X-C chemokine receptor type 4 (CXCR4) expression in CB-CD34＋ cells as well as in 293T and TF-1 cell lines. Since CXCR4 is a specific receptor for the stromal cell derived factor-1 (SDF-1) chemotactic factor, we investigated whether sense miR-9 and antisense miR-9 influenced CXCR4-mediated chemotactic mobility of primary CB CD34＋ cells and TF-1 cells. Ectopic overexpression of sense miR-9 and antisense miR-9 respectively down- and up-regulated SDF-1-mediated chemotactic cell mobility. To our knowledge, this study is the first to report that miR-9 may play a role in regulating CXCR4 expression and SDF-1-mediated chemotactic activity of CB CD34＋ cells.
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    Phosphatase of regenerating liver: a novel target for cancer therapy
    (Taylor & Francis, 2014-05) Campbell, Amanda M.; Zhang, Zhong-Yin; Biochemistry & Molecular Biology, School of Medicine
    INTRODUCTION: Phosphatases of regenerating livers (PRLs) are novel oncogenes that interact with many well-established cell signaling pathways that are misregulated in cancer, and are known to drive cancer metastasis when overexpressed. AREAS COVERED: This review covers basic information of the discovery and characteristics of the PRL family. We also report findings on the role of PRL in cancer, cell functions and cell signaling. Furthermore, PRL's suitability as a novel drug target is discussed along with current methods being developed to facilitate PRL inhibition. EXPERT OPINION: PRLs show great potential as novel drug targets for anticancer therapeutics. Studies indicate that PRL can perturb major cancer pathways such as Src/ERK1/2 and PTEN/PI3K/Akt. Upregulation of PRLs has also been shown to drive cancer metastasis. However, in order to fully realize its therapeutic potential, a deeper understanding of the function of PRL in normal tissue and in cancer must be obtained. Novel and integrated biochemical, chemical, biological, and genetic approaches will be needed to identify PRL substrate(s) and to provide proof-of-concept data on the druggability of the PRL phosphatases.
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    Phosphatidylethanolamines Are Associated with Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Adults and Induce Liver Cell Metabolic Perturbations and Hepatic Stellate Cell Activation
    (MDPI, 2023-01-05) Shama, Samaa; Jang, Hyejeong; Wang, Xiaokun; Zhang, Yang; Shahin, Nancy Nabil; Motawi, Tarek Kamal; Kim, Seongho; Gawrieh, Samer; Liu, Wanqing; Medicine, School of Medicine
    Pathogenesis roles of phospholipids (PLs) in nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This study investigated the role of PLs in the progression of NAFLD among obese individuals via studying the alterations in serum PL composition throughout the spectrum of disease progression and evaluating the effects of specific phosphatidylethanolamines (PEs) on FLD development in vitro. A total of 203 obese subjects, who were undergoing bariatric surgery, were included in this study. They were histologically classified into 80 controls (C) with normal liver histology, 93 patients with simple hepatic steatosis (SS), 16 with borderline nonalcoholic steatohepatitis (B-NASH) and 14 with progressive NASH (NASH). Serum PLs were profiled by automated electrospray ionization tandem mass spectrometry (ESI-MS/MS). HepG2 (hepatoma cells) and LX2 (immortalized hepatic stellate cells or HSCs) were used to explore the roles of PL in NAFLD/NASH development. Several PLs and their relative ratios were significantly associated with NAFLD progression, especially those involving PE. Incubation of HepG2 cells with two phosphatidylethanolamines (PEs), PE (34:1) and PE (36:2), resulted in significant inhibition of cell proliferation, reduction of mitochondrial mass and membrane potential, induction of lipid accumulation and mitochondrial ROS production. Meanwhile, treatment of LX2 cells with both PEs markedly increased cell activation and migration. These effects were associated with a significant change in the expression levels of genes involved in lipogenesis, lipid oxidation, autophagy, apoptosis, inflammation, and fibrosis. Thus, our study demonstrated that elevated level of PEs increases susceptibility to the disease progression of obesity associated NAFLD, likely through a causal cascade of impacts on the function of different liver cells.
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    Understanding the biological function of phosphatases of regenerating liver, from biochemistry to physiology
    (2014-07) Bai, Yunpeng; Zhang, Zhong-Yin; Quilliam, Lawrence; Shou, Weinian; Dong, X. Charlie
    Phosphatases of regenerating liver, consisting of PRL-1, PRL-2 and PRL-3, belong to a novel protein tyrosine phosphatases subfamily, whose overexpression promotes cell proliferation, migration and invasion and contributes to tumorigenesis and metastasis. However, although great efforts have been made to uncover the biological function of PRLs, limited knowledge is available on the underlying mechanism of PRLs’ actions, therapeutic value by targeting PRLs, as well as the physiological function of PRLs in vivo. To answer these questions, we first screened a phage display library and identified p115 RhoGAP as a novel PRL-1 binding partner. Mechanistically, we demonstrated that PRL-1 activates RhoA and ERK1/2 by decreasing the association between active RhoA with GAP domain of p115 RhoGAP, and displacing MEKK1 from the SH3 domain of p115 RhoGAP, respectively, leading to enhanced cell proliferation and migration. Secondly, structure-based virtual screening was employed to discover small molecule inhibitors blocking PRL-1 trimer formation which has been suggested to play an important role for PRL-1 mediated oncogenesis. We identified Cmpd-43 as a novel PRL-1 trimer disruptor. Structural study demonstrated the binding mode of PRL-1 with the trimer disruptor. Most importantly, cellular data revealed that Cmpd-43 inhibited PRL-1 induced cell proliferation and migration in breast cancer cell line MDA-MB-231 and lung cancer cell line H1299. Finally, in order to investigate the physiological function of PRLs, we generated mouse knockout models for Prl-1, Prl-2 and Prl-3. Although mice deficient for Prl-1 and Prl-3 were normally developed, Prl-2-null mice displayed growth retardation, impaired male reproductive ability and insufficient hematopoiesis. To further investigate the in vivo function of Prl-1, we generated Prl-1-/-/Prl-2+/- and Prl-1+/-/Prl-2-/- mice. Similar to Prl-2 deficient male mice, Prl-1-/-/Prl-2+/- males also have impaired spermatogenesis and reproductivity. More strikingly, Prl-1+/-/Prl-2-/- mice are completely infertile, suggesting that, in addition to PRL-2, PRL-1 also plays an important role in maintaining normal testis function. In summary, these studies demonstrated for the first time that PRL-1 activates ERK1/2 and RhoA through the novel interaction with p115 RhoGAP, targeting PRL-1 trimer interface is a novel anti-cancer therapeutic treatment and both PRL-1 and PRL-2 contribute to spermatogenesis and male mice reproductivity.