scholarly journals A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation

2021 ◽  
Vol 11 ◽  
Author(s):  
Tyler A. Allen ◽  
Mark M. Cullen ◽  
Nathan Hawkey ◽  
Hiroyuki Mochizuki ◽  
Lan Nguyen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Circulating Tumor Cell ◽  
Transgenic Zebrafish ◽  
Matrix Remodeling ◽  
Cellular Mechanisms ◽  
Zebrafish Model ◽  
Cell Clusters ◽  
Metastatic Colonization ◽  
Multistep Process

Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under intravital imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican (VCAN) as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

scholarly journals Scar Formation: Cellular Mechanisms

2020 ◽  
pp. 19-26
Author(s):  
Ian A. Darby ◽  
Alexis Desmoulière
Keyword(s):  
Extracellular Matrix ◽  
Tissue Repair ◽  
New Drugs ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Matrix Remodeling ◽  
Hypertrophic Scars ◽  
Cellular Mechanisms ◽  
Skin Repair ◽  
Cell Quiescence ◽  
Key Players

AbstractFibroblasts are key players in the maintenance of skin homeostasis and in orchestrating physiological tissue repair. Fibroblasts secrete and are embedded in a sophisticated extracellular matrix, and a complex and interactive dialogue exists between fibroblasts and their microenvironment. In addition to the secretion of the extracellular matrix, fibroblasts and myofibroblasts secrete extracellular matrix remodeling enzymes, matrix metalloproteinases and their inhibitors, and tissue inhibitors of metalloproteinases and are thus able to remodel the extracellular matrix. Myofibroblasts and their microenvironment form a network that evolves during tissue repair. This network has reciprocal actions affecting cell differentiation, cell proliferation, cell quiescence, or apoptosis and has actions on growth factor bioavailability by binding, sequestration, and activation. Mechanical forces also play a role in regulating the myofibroblast phenotype as cells are subjected to mechanical stress and mechanical signaling is activated. Innervation is also involved in both skin repair processes and differentiation of myofibroblasts. In pathological situations, for example, in excessive scarring, the dialogue between myofibroblasts and their microenvironment can be altered or disrupted, leading to defects in tissue repair or to pathological scarring, such as that seen in hypertrophic scars. Better understanding of the intimate dialogue between myofibroblasts and their local microenvironment is needed and will be important in aiding the identification of new therapeutic targets and discovery of new drugs to treat or prevent aberrant tissue repair and scarring.

scholarly journals Novel approaches in cancer management with circulating tumor cell clusters

2019 ◽  
Vol 4 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Peyman Rostami ◽  
Navid Kashaninejad ◽  
Khashayar Moshksayan ◽  
Mohammad Said Saidi ◽  
Bahar Firoozabadi ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Circulating Tumor Cell ◽  
Cell Clusters ◽  
Cancer Management ◽  
Novel Approaches

En Route to Metastasis: Circulating Tumor Cell Clusters and Epithelial-to-Mesenchymal Transition

2015 ◽  
Vol 1 (1) ◽  
pp. 44-52 ◽  
Author(s):  
Nicola Aceto ◽  
Mehmet Toner ◽  
Shyamala Maheswaran ◽  
Daniel A. Haber
Keyword(s):  
Tumor Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Circulating Tumor Cell ◽  
Mesenchymal Transition ◽  
Cell Clusters

scholarly journals Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression

2016 ◽  
Vol 6 (5) ◽  
pp. 516-531 ◽  
Author(s):  
Madeleine J. Oudin ◽  
Oliver Jonas ◽  
Tatsiana Kosciuk ◽  
Liliane C. Broye ◽  
Bruna C. Guido ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tumor Cell ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Metastatic Progression

scholarly journals Intratumor Heterogeneity and Circulating Tumor Cell Clusters

2017 ◽  
Author(s):  
Zafarali Ahmed ◽  
Simon Gravel
Keyword(s):  
Tumor Cell ◽  
Growth Parameters ◽  
Numerical Models ◽  
Circulating Tumor Cell ◽  
Intratumor Heterogeneity ◽  
Tumor Evolution ◽  
List Type ◽  
Cell Turnover ◽  
Cell Clusters ◽  
Spatial Trends

SummaryGenetic diversity plays a central role in tumor progression, metastasis, and resistance to treatment. Experiments are shedding light on this diversity at ever finer scales, but interpretation is challenging. Using recent progress in numerical models, we simulate macroscopic tumors to investigate the interplay between growth dynamics, microscopic composition, and circulating tumor cell cluster diversity. We find that modest differences in growth parameters can profoundly change microscopic diversity. Simple outwards expansion leads to spatially segregated clones and low diversity, as expected. However, a modest cell turnover can result in an increased number of divisions and mixing among clones resulting in increased microscopic diversity in the tumor core. Using simulations to estimate power to detect such spatial trends, we find that multiregion sequencing data from contemporary studies is marginally powered to detect the predicted effects. Slightly larger samples, improved detection of rare variants, or sequencing of smaller biopsies or circulating tumor cell clusters would allow one to distinguish between leading models of tumor evolution. The genetic composition of circulating tumor cell clusters, which can be obtained from non-invasive blood draws, is therefore informative about tumor evolution and its metastatic potential.HighlightsNumerical and theoretical models show interaction of front expansion, mutation, and clonal mixing in shaping tumor heterogeneity.Cell turnover increases intratumor heterogeneity.Simulated circulating tumor cell clusters and microbiopsies exhibit substantial diversity with strong spatial trends.Simulations suggest attainable sampling schemes able to distinguish between prevalent tumor growth models.

scholarly journals Regulation of Myocardial Extracellular Matrix Dynamic Changes in Myocardial Infarction and Postinfarct Remodeling

2020 ◽  
Vol 16 (1) ◽  
pp. 11-24 ◽  
Author(s):  
Alexey Ushakov ◽  
Vera Ivanchenko ◽  
Alina Gagarina
Keyword(s):  
Myocardial Infarction ◽  
Extracellular Matrix ◽  
Transforming Growth Factor ◽  
Clinical Manifestations ◽  
Pivotal Role ◽  
Matrix Remodeling ◽  
Matricellular Proteins ◽  
Myocardial Repair ◽  
Cellular Mechanisms

The article represents literature review dedicated to molecular and cellular mechanisms underlying clinical manifestations and outcomes of acute myocardial infarction. Extracellular matrix adaptive changes are described in detail as one of the most important factors contributing to healing of damaged myocardium and post-infarction cardiac remodeling. Extracellular matrix is reviewed as dynamic constantly remodeling structure that plays a pivotal role in myocardial repair. The role of matrix metalloproteinases and their tissue inhibitors in fragmentation and degradation of extracellular matrix as well as in myocardium healing is discussed. This review provides current information about fibroblasts activity, the role of growth factors, particularly transforming growth factor β and cardiotrophin-1, colony-stimulating factors, adipokines and gastrointestinal hormones, various matricellular proteins. In conclusion considering the fact that dynamic transformation of extracellular matrix after myocardial ischemic damage plays a pivotal role in myocardial infarction outcomes and prognosis, we suggest a high importance of further investigation of mechanisms underlying extracellular matrix remodeling and cell-matrix interactions in cardiovascular diseases.

Sign in / Sign up

Export Citation Format

Share Document