mesenchymal_motion   9

Autocrine Fibronectin Inhibits Breast Cancer Metastasis | Molecular Cancer Research
Paradoxically in METABRIc tumors with high FN have worse outcome but in MCF10 derivatives high FN inhibits metastasis but correlates with mesenchymal nature. In cocultures FN production stimulates invasion of the non mesenchymal cells - possible mediator of flow effects? Upregulating FN suppressed Ecad expression and vice versa.

Both epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) are linked to metastasis via their ability to increase invasiveness and enhance tumor-initiating capacity. Growth factors, cytokines, and chemotherapies present in the tumor microenvironment (TME) are capable of inducing EMT, but the role of the extracellular matrix (ECM) in this process remains poorly understood. Here, a novel tessellated three-dimensional (3D) polymer scaffolding is used to produce a fibrillar fibronectin matrix that induces an EMT-like event that includes phosphorylation of STAT3 and requires expression of β1 integrin. Consistent with these findings, analysis of the METABRIC dataset strongly links high-level fibronectin (FN) expression to decreased patient survival. In contrast, in vitro analysis of the MCF-10A progression series indicated that intracellular FN expression was associated with nonmetastatic cells. Therefore, differential bioluminescent imaging was used to track the metastasis of isogenic epithelial and mesenchymal cells within heterogeneous tumors. Interestingly, mesenchymal tumor cells do not produce a FN matrix and cannot complete the metastatic process, even when grown within a tumor containing epithelial cells. However, mesenchymal tumor cells form FN-containing cellular fibrils capable of supporting the growth and migration of metastatic-competent tumor cells. Importantly, depletion of FN allows mesenchymal tumor cells to regain epithelial characteristics and initiate in vivo tumor growth within a metastatic microenvironment.
fibronectin  EMT  MET  Metastasis  mesenchymal_motion 
february 2019 by Segalllab
A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma | Cancer Research
radiation increases MRCK (which is up at the edges of invasive tumors also) and cdc42 to mrck may lead to mesenchymal invasion

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment. Here, we demonstrate an essential role of the actin-myosin regulatory kinase myotonic dystrophy kinase-related CDC42-binding kinase (MRCK) in mediating the proinvasive effects of radiation. MRCK-mediated invasion occurred via downstream signaling to effector molecules MYPT1 and MLC2. MRCK was activated by clinically relevant doses per fraction of radiation, and this activation was concomitant with an increase in GBM cell motility and invasion. Furthermore, ablation of MRCK activity either by RNAi or by inhibition with the novel small-molecule inhibitor BDP-9066 prevented radiation-driven increases in motility both in vitro and in a clinically relevant orthotopic xenograft model of GBM. Crucially, treatment with BDP-9066 in combination with RT significantly increased survival in this model and markedly reduced infiltration of the contralateral cerebral hemisphere.
mrck  Glioblastoma  invasion  mesenchymal_motion  radiation  cdc42 
february 2019 by Segalllab
Telomerase reverse transcriptase coordinates with the epithelial-to-mesenchymal transition through a feedback loop to define properties of breast cancer stem cells | Biology Open
All done with 231 cells. interesting that hTERT expression correlates with mesenchymal and stem characteristics

Telomerase and its core component, telomerase reverse transcriptase (hTERT), are critical for stem cell compartment integrity. Normal adult stem cells have the longest telomeres in a given tissue, a property mediated by high hTERT expression and high telomerase enzymatic activity. In contrast, cancer stem cells (CSCs) have short telomeres despite high expression of hTERT, indicating that the role of hTERT in CSCs is not limited to telomere elongation and/or maintenance. The function of hTERT in CSCs remains poorly understood. Here, we knocked down hTERT expression in CSCs and observed a morphological shift to a more epithelial phenotype, suggesting a role for hTERT in the epithelial-to-mesenchymal transition (EMT) of CSCs. Therefore, in this study, we systematically explored the relationship between hTERT and EMT and identified a reciprocal, bi-directional feedback loop between hTERT and EMT in CSCs. We found that hTERT expression is mutually exclusive to the mesenchymal phenotype and that, reciprocally, loss of the mesenchymal phenotype represses hTERT expression. We also showed that hTERT plays a critical role in the expression of key CSC markers and nuclear β-catenin localization, increases the percentage of cells with side-population properties, and upregulates the CD133 expression. hTERT also promotes chemoresistance properties, tumorsphere formation and other important functional CSC properties. Subsequently, hTERT knockdown leads to the loss of the above advantages, indicating a loss of CSC properties. Our findings suggest that targeting hTERT might improve CSCs elimination by transitioning them from the aggressive mesenchymal state to a more steady epithelial state, thereby preventing cancer progression.
231_cells  EMT  mesenchymal_motion  stem_cells  hTERT 
february 2019 by Segalllab
Hic-5 expression is a major indicator of cancer cell morphology, migration, and plasticity in three-dimensional matrices | Molecular Biology of the Cell
worked with 231 and other cell lines. HIC5 induces mesenchymal while paxillin induces amoeboid motility and speicific tyrosines on paxillin are important as well. vinculin mediates hic5 induced mesenchymal motility.

"The focal adhesion proteins Hic-5 and paxillin have been previously identified as key regulators of MDA-MB-231 breast cancer cell migration and morphologic mesenchymal-amoeboid plasticity in three-dimensional (3D) extracellular matrices (ECMs). However, their respective roles in other cancer cell types have not been evaluated. Herein, utilizing 3D cell–derived matrices and fibronectin-coated one-dimensional substrates, we show that across a variety of cancer cell lines, the level of Hic-5 expression serves as the major indicator of the cells primary morphology, plasticity, and in vitro invasiveness. Domain mapping studies reveal sites critical to the functions of both Hic-5 and paxillin in regulating phenotype, while ectopic expression of Hic-5 in cell lines with low endogenous levels of the protein is sufficient to induce a Rac1-dependent mesenchymal phenotype and, in turn, increase amoeboid-mesenchymal plasticity and invasion. We show that the activity of vinculin, when coupled to the expression of Hic-5 is required for the mesenchymal morphology in the 3D ECM. Taken together, our results identify Hic-5 as a critical modulator of tumor cell phenotype that could be utilized in predicting tumor cell migratory and invasive behavior in vivo.
231_cells  amoeboid_motion  paxillin  hic5  vinculin  mesenchymal_motion 
july 2018 by Segalllab
Confinement and Low Adhesion Induce Fast Amoeboid Migration of Slow Mesenchymal Cells
Interesting - tumor cells are more inclined to switch to amoeboid motility in confined spaces if they cannot form focal adhesions.
focal_adhesions  amoeboid_motion  mesenchymal_motion  myosin 
march 2015 by Segalllab
Laboratory Investigation - Matrikine and matricellular regulators of EGF receptor signaling on cancer cell migration and invasion
Discussion of the role of ECM matrix proteins in modifying cell motility, with the additional twist that proteolysis during wound healing may expose EGF like domains that can bind and activate the EGFR. "What is common for all of the above-discussed matricellular proteins that promote migration and invasion is that, in addition to regions binding to β1 integrin, they all have EGFL domains. TNC, TSP1, and Ln-332 have EGFL that have been shown to bind and activate EGFR, whereas SPARC and fibulins have EGFL that have not been examined for growth factor receptor binding. Furthermore, they all bind syndecans and induce or activate various MMPs that may in turn clip the molecules to expose these cryptic signaling moieties. TSP1 and SPARC also activate uPA/uPAR signaling and the generation of active HGF/Scatter Factor"."
EGFR  ecm  motility  mesenchymal_motion  amoeboid_motion 
july 2014 by Segalllab
β-Catenin Inhibitor ICAT Modulates the Invasive Motility of Melanoma Cells
an extra twist on NEDD9 - it is regulated by beta catenin TCF/LEF, but downregulation of it converts melanoma cells from a mesenchymal to more amoeboid motility.
nedd9  mesenchymal_motion  amoeboid_motion  bcatenin  tcf/lef 
june 2014 by Segalllab

related tags

231_cells  amoeboid_motion  bcatenin  cdc42  ecm  egfr  emt  fibronectin  focal_adhesions  general  glioblastoma  hic5  htert  invasion  met  metastasis  motility  mrck  myosin  nedd9  non_canonical  paxillin  radiation  snail  stem_cells  tcf/lef  tgfbeta  vinculin  wnt11  wnt_signaling 

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