scholarly journals Regulation of ATP utilization during metastatic cell migration by collagen architecture

2018 ◽  
Vol 29 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Matthew R. Zanotelli ◽  
Zachary E. Goldblatt ◽  
Joseph P. Miller ◽  
Francois Bordeleau ◽  
Jiahe Li ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Three Dimensional ◽  
Migration And Invasion ◽  
Energy Regulation ◽  
Cancer Cell Migration ◽  
In Cells

Cell migration in a three-dimensional matrix requires that cells either remodel the surrounding matrix fibers and/or squeeze between the fibers to move. Matrix degradation, matrix remodeling, and changes in cell shape each require cells to expend energy. While significant research has been performed to understand the cellular and molecular mechanisms guiding metastatic migration, less is known about cellular energy regulation and utilization during three-dimensional cancer cell migration. Here we introduce the use of the genetically encoded fluorescent biomarkers, PercevalHR and pHRed, to quantitatively assess ATP, ADP, and pH levels in MDA-MB-231 metastatic cancer cells as a function of the local collagen microenvironment. We find that the use of the probe is an effective tool for exploring the thermodynamics of cancer cell migration and invasion. Specifically, we find that the ATP:ADP ratio increases in cells in denser matrices, where migration is impaired, and it decreases in cells in aligned collagen matrices, where migration is facilitated. When migration is pharmacologically inhibited, the ATP:ADP ratio decreases. Together, our data indicate that matrix architecture alters cellular energetics and that intracellular ATP:ADP ratio is related to the ability of cancer cells to effectively migrate.

scholarly journals The C-Terminus Tail Regulates ERK3 Kinase Activity and Its Ability in Promoting Cancer Cell Migration and Invasion

2020 ◽  
Vol 21 (11) ◽  
pp. 4044 ◽  
Author(s):  
Lobna Elkhadragy ◽  
Hadel Alsaran ◽  
Weiwen Long
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Cell Migration And Invasion ◽  
C Terminus

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family. It harbors a kinase domain in the N-terminus and a long C-terminus extension. The C-terminus extension comprises a conserved in ERK3 and ERK4 (C34) region and a unique C-terminus tail, which was shown to be required for the interaction of ERK3 with the cytoskeletal protein septin 7. Recent studies have elucidated the role of ERK3 signaling in promoting the motility and invasiveness of cancer cells. However, little is known about the intramolecular regulation of the enzymatic activity and cellular functions of ERK3. In this study, we investigated the role of the elongated C-terminus extension in regulating ERK3 kinase activity and its ability to promote cancer cell migration and invasion. Our study revealed that the deletion of the C-terminus tail greatly diminishes the ability of ERK3 to promote the migration and invasion of lung cancer cells. We identified two molecular mechanisms underlying this effect. Firstly, the deletion of the C-terminus tail decreases the kinase activity of ERK3 towards substrates, including the oncogenic protein steroid receptor co-activator 3 (SRC-3), an important downstream target for ERK3 signaling in cancer. Secondly, in line with the previous finding that the C-terminus tail mediates the interaction of ERK3 with septin 7, we found that the depletion of septin 7 abolished the ability of ERK3 to promote migration, indicating that septin 7 acts as a downstream effector for ERK3-induced cancer cell migration. Taken together, the findings of this study advance our understanding of the molecular regulation of ERK3 signaling by unraveling the role of the C-terminus tail in regulating ERK3 kinase activity and functions in cancer cells. These findings provide useful insights for the development of therapeutic agents targeting ERK3 signaling in cancer.

A fluorescence nanoprobe for detecting the effect of different oxygen and nutrient conditions on breast cancer cells migration and invasion

2021 ◽  
Author(s):  
Ping Zhou ◽  
Bo Liu ◽  
Mingming Luan ◽  
Na Li ◽  
Bo Tang
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Tumor Metastasis ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Fluorescence Nanoprobe

Cancer cell migration and invasion are initial steps for tumor metastasis that increases patient mortality. Tumor microenvironment is characterized by hypoxic and low nutrient-containing. Previous studies have suggested that hypoxia...

scholarly journals A Novel 3D Model for Visualization and Tracking of Fibroblast-Guided Directional Cancer Cell Migration

Biology ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 328
Author(s):  
Yihe Zhang ◽  
Bingjie Jiang ◽  
Meng Huee Lee
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Physical Contact ◽  
Physical Interaction ◽  
Matrix Remodeling ◽  
Cancer Cell Migration ◽  
Cell Type

Stromal fibroblasts surrounding cancer cells are a major and important constituent of the tumor microenvironment not least because they contain cancer-associated fibroblasts, a unique fibroblastic cell type that promotes tumorigenicity through extracellular matrix remodeling and secretion of soluble factors that stimulate cell differentiation and invasion. Despite much progress made in understanding the molecular mechanisms that underpin fibroblast–tumor cross-talk, relatively little is known about the way the two cell types interact from a physical contact perspective. In this study, we report a novel three-dimensional dumbbell model that would allow the physical interaction between the fibroblasts and cancer cells to be visualized and monitored by microscopy. To achieve the effect, the fibroblasts and cancer cells in 50% Matrigel suspension were seeded as independent droplets in separation from each other. To allow for cell migration and interaction, a narrow passage of Matrigel causeway was constructed in between the droplets, effectively molding the gel into the shape of a dumbbell. Under time-lapse microscopy, we were able to visualize and image the entire process of fibroblast-guided cancer cell migration event, from initial vessel-like structure formation by the fibroblasts to their subsequent invasion across the causeway, attracting and trapping the cancer cells in the process. Upon prolonged culture, the entire population of fibroblasts eventually infiltrated across the passage and condensed into a spheroid-like cell mass, encapsulating the bulk of the cancer cell population within. Suitable for almost every cell type, our model has the potential for a wider application as it can be adapted for use in drug screening and the study of cellular factors involved in cell–cell attraction.

scholarly journals p62 is Negatively Implicated in the TRAF6-BECN1 Signaling Axis for Autophagy Activation and Cancer Progression by Toll-Like Receptor 4 (TLR4)

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1142 ◽  
Author(s):  
Mi-Jeong Kim ◽  
Yoon Min ◽  
Ji Seon Im ◽  
Juhee Son ◽  
Joo Sang Lee ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
A549 Cells ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Cell Migration And Invasion ◽  
Signaling Axis

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 negatively regulates Toll-like receptor 4 (TLR4)-mediated signaling via TRAF6-ECSIT signaling axis, we herein investigated whether p62 is functionally implicated in the TRAF6-BECN1 signaling axis, thereby regulating cancer cell migration and invasion. p62 interacted with TRAF6 and BECN1, to interrupt the functional associations required for TRAF6-BECN1 complex formation, leading to inhibitions of BECN1 ubiquitination and autophagy activation. Importantly, p62-deficient cancer cells, such as p62-knockdown (p62KD) SK-HEP-1, p62KD MDA-MB-231, and p62-knockout (p62KO) A549 cells, showed increased activation of autophagy induced by TLR4 stimulation, suggesting that p62 negatively regulates autophagy activation. Moreover, these p62-deficient cancer cells exhibited marked increases in cell migration and invasion in response to TLR4 stimulation. Collectively, these results suggest that p62 is negatively implicated in the TRAF6-BECN1 signaling axis, thereby inhibiting cancer cell migration and invasion regulated by autophagy activation in response to TLR4 stimulation.

scholarly journals Modeling the Mechanobiology of Cancer Cell Migration Using 3D Biomimetic Hydrogels

Gels ◽  
2021 ◽  
Vol 7 (1) ◽  
pp. 17
Author(s):  
Xabier Morales ◽  
Iván Cortés-Domínguez ◽  
Carlos Ortiz-de-Solorzano
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Chemical Composition ◽  
Cancer Cells ◽  
Cancer Cell ◽  
State Of The Art ◽  
Three Dimensional ◽  
Cancer Cell Migration ◽  
Hydrogel Scaffolds ◽  
Metastatic Process

Understanding how cancer cells migrate, and how this migration is affected by the mechanical and chemical composition of the extracellular matrix (ECM) is critical to investigate and possibly interfere with the metastatic process, which is responsible for most cancer-related deaths. In this article we review the state of the art about the use of hydrogel-based three-dimensional (3D) scaffolds as artificial platforms to model the mechanobiology of cancer cell migration. We start by briefly reviewing the concept and composition of the extracellular matrix (ECM) and the materials commonly used to recreate the cancerous ECM. Then we summarize the most relevant knowledge about the mechanobiology of cancer cell migration that has been obtained using 3D hydrogel scaffolds, and relate those discoveries to what has been observed in the clinical management of solid tumors. Finally, we review some recent methodological developments, specifically the use of novel bioprinting techniques and microfluidics to create realistic hydrogel-based models of the cancer ECM, and some of their applications in the context of the study of cancer cell migration.

scholarly journals Scaffold Protein RACK1 inhibitor compounds prevent the Focal Adhesion Kinase mediated breast cancer cell migration and invasion potential

2021 ◽  
Author(s):  
Hemayet Ullah ◽  
Nagib Ahsan ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Focal Adhesion Kinase ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Focal Adhesion ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Inhibitor Compounds

Scaffold protein RACK1 mediates cancer cell migration mostly through regulation of focal adhesion (FA) assembly by promoting a focal adhesion kinase (FAK) activation downstream of the integrin clustering and adhesion at the extracellular matrix (ECM). Here we demonstrated the efficacy of our recently developed RACK1 Y246 phosphorylation inhibitor compounds (SD29 and SD29-14) to inhibit the migration and invasion of MCF7 and MDA-MB-231 breast cancer cell lines. Using multiple assays, our results confirmed that inhibitor compounds effectively prevent the filopodia/lamellipodia development and inhibits the migration of breast cancer cells. A mechanistic model of the inhibitor compounds has been developed. Migration and invasion capabilities of the cancer cells define the metastasis of cancer. Thus, our results suggest a potential therapeutic mechanism of the inhibitors to prevent metastasis in diverse cancers.

Matrix metalloproteinase targeted peptide vesicles for delivering anticancer drugs

2018 ◽  
Vol 54 (67) ◽  
pp. 9309-9312 ◽  
Author(s):  
Debmalya Bhunia ◽  
Krishnangsu Pradhan ◽  
Gaurav Das ◽  
Subhajit Ghosh ◽  
Prasenjit Mondal ◽  
...  
Keyword(s):  
Cell Migration ◽  
Matrix Metalloproteinase ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Cancer Cell ◽  
Metastatic Cancer ◽  
Cancer Cell Migration ◽  
Apoptotic Death ◽  
Metastatic Cancer Cell ◽  
3D Spheroids

A matrix metalloproteinase (MMP) targeted tetrapeptide vesicle strongly binds at a MMP9 enzymatic site and delivers an anticancer drug into cancer cells. Further, it induces superior apoptotic death and inhibits the metastatic cancer cell migration and growth of multicellular 3D spheroids.

scholarly journals Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy

2014 ◽  
Vol 11 (99) ◽  
pp. 20140638 ◽  
Author(s):  
Wei Sun ◽  
Chwee Teck Lim ◽  
Nicholas Agung Kurniawan
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Primary Tumour ◽  
Three Dimensional ◽  
Drug Efficacy ◽  
Biophysical Properties ◽  
Invasion Mechanisms

Cancer metastasis involves the dissemination of cancer cells from the primary tumour site and is responsible for the majority of solid tumour-related mortality. Screening of anti-metastasis drugs often includes functional assays that examine cancer cell invasion inside a three-dimensional hydrogel that mimics the extracellular matrix (ECM). Here, we built a mechanically tuneable collagen hydrogel model to recapitulate cancer spreading into heterogeneous tumour stroma and monitored the three-dimensional invasion of highly malignant breast cancer cells, MDA-MB-231. Migration assays were carried out in the presence and the absence of drugs affecting four typical molecular mechanisms involved in cell migration, as well as under five ECMs with different biophysical properties. Strikingly, the effects of the drugs were observed to vary strongly with matrix mechanics and microarchitecture, despite the little dependence of the inherent cancer cell migration on the ECM condition. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. The results corroborate the ability of cancer cells to switch their multiple invasion mechanisms depending on ECM condition, thus suggesting the importance of factoring in the biophysical properties of the ECM in anti-metastasis drug screenings.

scholarly journals Thy-1 (CD90)-Induced Metastatic Cancer Cell Migration and Invasion Are β3 Integrin-Dependent and Involve a Ca2+/P2X7 Receptor Signaling Axis

2021 ◽  
Vol 8 ◽  
Author(s):  
Marianne Brenet ◽  
Samuel Martínez ◽  
Ramón Pérez-Nuñez ◽  
Leonardo A. Pérez ◽  
Pamela Contreras ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
P2x7 Receptor ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
Cancer Cell Migration ◽  
Cell Migration And Invasion ◽  
Signaling Axis

Cancer cell adhesion to the vascular endothelium is an important step in tumor metastasis. Thy-1 (CD90), a cell adhesion molecule expressed in activated endothelial cells, has been implicated in melanoma metastasis by binding to integrins present in cancer cells. However, the signaling pathway(s) triggered by this Thy-1-Integrin interaction in cancer cells remains to be defined. Our previously reported data indicate that Ca2+-dependent hemichannel opening, as well as the P2X7 receptor, are key players in Thy-1-αVβ3 Integrin-induced migration of reactive astrocytes. Thus, we investigated whether this signaling pathway is activated in MDA-MB-231 breast cancer cells and in B16F10 melanoma cells when stimulated with Thy-1. In both cancer cell types, Thy-1 induced a rapid increase in intracellular Ca2+, ATP release, as well as cell migration and invasion. Connexin and Pannexin inhibitors decreased cell migration, implicating a requirement for hemichannel opening in Thy-1-induced cell migration. In addition, cell migration and invasion were precluded when the P2X7 receptor was pharmacologically blocked. Moreover, the ability of breast cancer and melanoma cells to transmigrate through an activated endothelial monolayer was significantly decreased when the β3 Integrin was silenced in these cancer cells. Importantly, melanoma cells with silenced β3 Integrin were unable to metastasize to the lung in a preclinical mouse model. Thus, our results suggest that the Ca2+/hemichannel/ATP/P2X7 receptor-signaling axis triggered by the Thy-1-αVβ3 Integrin interaction is important for cancer cell migration, invasion and transvasation. These findings open up the possibility of therapeutically targeting the Thy-1-Integrin signaling pathway to prevent metastasis.

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