Paxillin Promotes Breast Tumor Collective Cell Invasion through Maintenance of Adherens Junction Integrity

2021 ◽  
Author(s):  
Weiyi Xu ◽  
Kyle M. Alpha ◽  
Nicholas M. Zehrbach ◽  
Christopher E. Turner
Keyword(s):  
Tumor Cell ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Breast Tumor ◽  
Rho Gtpase ◽  
Adherens Junction ◽  
Tumor Cell Migration ◽  
Tumor Organoids ◽  
E Cadherin

Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among different human cancers, but its role in tumor progression is unclear. Herein, we utilize a newly generated PyMT mammary tumor mouse model with conditional paxillin ablation in breast tumor epithelial cells, combined with in vitro 3D tumor organoids invasion analysis and 2D calcium switch assays, to assess the roles for paxillin in breast tumor cell invasion. Paxillin had little effect on primary tumor initiation and growth but is critical for the formation of distant lung metastasis. In paxillin-depleted 3D tumor organoids, collective cell invasion was substantially perturbed. Two-dimensional cell culture revealed paxillin-dependent stabilization of adherens junctions (AJ). Mechanistically, paxillin is required for AJ assembly through facilitating E-cadherin endocytosis and recycling and HDAC6-mediated microtubule acetylation. Furthermore, Rho GTPase activity analysis and rescue experiments with a RhoA activator or Rac1 inhibitor suggest paxillin is potentially regulating the E-cadherin-dependent junction integrity and contractility through control of the balance of RhoA and Rac1 activities. Together, these data highlight new roles for paxillin in the regulation of cell-cell adhesion and collective tumor cell migration to promote the formation of distance organ metastases. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

scholarly journals Tumor cell-derived SPON2 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by activating PYK2 in CRC

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chengmei Huang ◽  
Ruizhang Ou ◽  
Xiaoning Chen ◽  
Yaxin Zhang ◽  
Jiexi Li ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cancer Progression ◽  
Transendothelial Migration ◽  
Tumor Formation ◽  
Integrin Β1 ◽  
Tumor Cell Migration ◽  
M2 Polarization ◽  
Migration Assays

Abstract Background Tumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment. Tumor cell-derived spondin 2 (SPON2) is an extracellular matrix glycoprotein that has complicated roles in recruitment of macrophages and neutrophils during inflammation. Overexpression of SPON2 has been shown to promote tumor cell migration in colorectal cancer (CRC). However, the mechanism by which SPON2 regulates the accumulation of TAMs in the tumor microenvironment (TME) of CRC is unknown. Methods Immunohistochemistry was used to examine SPON2 expression in clinical CRC tissues. In vitro migration assays, transendothelial migration assays (iTEM), and cell adhesion assays were used to investigate the effects of SPON2 on monocyte/macrophage migration. Subcutaneous tumor formation and orthotopic implantation assays were performed in C57 BL/6 mice to confirm the effects of SPON2 on TAM infiltration in tumors. Results SPON2 expression is positively correlated with M2-TAM infiltration in clinical CRC tumors and poor prognosis of CRC patients. In addition, SPON2 promotes cytoskeletal remodeling and transendothelial migration of monocytes by activating integrin β1/PYK2 axis. SPON2 may indirectly induce M2-polarization through upregulating cytokines including IL10, CCL2 and CSF1 expression in tumor cells. Blocking M2 polarization and Macrophage depletion inhibited the SPON2-induced tumors growth and invasion. Furthermore, blocking the SPON2/integrin β1/PYK2 axis impairs the transendothelial migration of monocytes and cancer-promoting functions of TAMs in vivo. Conclusions Our findings demonstrate that SPON2-driven M2-TAM infiltration plays an important role during CRC tumor growth and metastasis. SPON2 may be a valuable biomarker guiding the use of macrophage-targeting strategies and a potential therapeutic target in advanced CRC.

scholarly journals ADAM9 silencing inhibits breast tumor cell invasion in vitro

Biochimie ◽  
2013 ◽  
Vol 95 (7) ◽  
pp. 1371-1378 ◽  
Author(s):  
Kelli Cristina Micocci ◽  
Ana Carolina Baptista Moreno Martin ◽  
Cyntia de Freitas Montenegro ◽  
Araceli Cristina Durante ◽  
Normand Pouliot ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Invasion ◽  
Breast Tumor ◽  
Tumor Cell Invasion ◽  
Breast Tumor Cell

Ionizing Radiation Enhances Breast Tumor Cell Migration In Vitro

2017 ◽  
Vol 188 (4) ◽  
pp. 381 ◽  
Author(s):  
Ada G. H. Young ◽  
Kevin L. Bennewith
Keyword(s):  
Cell Migration ◽  
Ionizing Radiation ◽  
Tumor Cell ◽  
Breast Tumor ◽  
Breast Tumor Cell ◽  
Tumor Cell Migration

scholarly journals Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Blood ◽  
2012 ◽  
Vol 119 (7) ◽  
pp. 1623-1633 ◽  
Author(s):  
Jan Van den Bossche ◽  
Bernard Malissen ◽  
Alberto Mantovani ◽  
Patrick De Baetselier ◽  
Jo A. Van Ginderachter
Keyword(s):  
Rho Gtpase ◽  
Nk Cell ◽  
Critical Role ◽  
Adherens Junction ◽  
Mononuclear Phagocyte ◽  
Alternatively Activated Macrophages ◽  
Junction Protein ◽  
E Cadherin

Abstract E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/β-catenin, PI3K/Akt, Rho GTPase, and NF-κB signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. E-cadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of β-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also E-cadherin–dependent. In addition, the E-cadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin–expressing DCs and macrophages. Here we discuss the regulation, function, and implications of E-cadherin expression in these central orchestrators of the immune system.

Elaeagnus Angustifolia: a Promising Medicinal Plant for Cancer Theraby

2020 ◽  
Author(s):  
Islam Mohamed ◽  
Ahmed Moahmed ◽  
Mennatallah Abdelkader ◽  
Alaaeldin Saleh ◽  
Ala-Eddin Al-Moustafa
Keyword(s):  
Cell Proliferation ◽  
Oral Cancer ◽  
Medicinal Plant ◽  
Cancer Progression ◽  
Plant Extract ◽  
Cell Invasion ◽  
Elaeagnus Angustifolia ◽  
Flower Extract ◽  
Inhibition Of Angiogenesis ◽  
E Cadherin

Introduction: Elaeagnus angustifolia (EA) is a medicinal plant that has been used for centuries in treating many human diseases, in the Middle East, including fever, amoebic dysentery, gastrointestinal problems. However, the effect of EA plant extract on human cancer progression especially oral malignancy has not been investigated yet. Thus, first we examined the effect of EA flower extract on angiogenesis in ovo, and on selected parameters in human oral cancer cells. Materials and methods: Chorioallantoic membranes (CAMs) of chicken embryos at 3-7 days of incubation were used to assess the effect EAflower plant extract on angiogenesis. Meanwhile, cell proliferation, soft agar, cell cycle, cell invasion and cell wounding assays were performed to explore the outcome of EA plant extract on FaDu and SCC25 oral cancer cell lines. On the other hand, western blot analysis was carried out to evaluate E-cadherin and Erk1/Erk2 expression and activation, respectively, in FaDu and SCC25 under the effect of EA extract. Results: Our data show that EA extract inhibits cell proliferation and colony formation, in addition to the initiation of Scell cycle arrest and reductionof G1/G2 phases. In parallel, EA extract provokes differentiation to an epithelial phenotype “mesenchymal-epithelial transition: MET” which is the opposite of “epithelial-mesenchymal transition, EMT”: an important event in cell invasion and metastasis. Thus, EA extract causes a dramatic decrease in cell motility and invasion abilities of FaDu and SCC25 cancer cells in comparison with their controls. These changes are accompanied by an up-regulation of E-cadherin expression. The molecular pathway analysis of the EA flower extract reveals that it can inhibit the phosphorylation of Erk1/Erk2, which could be behind the inhibition of angiogenesis, the initiation of MET event and the overexpression of E-cadherin. Conclusions: Our findings indicate that EA plant extract can downgrade human oral cancer progression by the inhibition of angiogenesis and cell invasion via Erk1/Erk2 signaling pathways.

scholarly journals Compensation mechanism in tumor cell migration

2003 ◽  
Vol 160 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Katarina Wolf ◽  
Irina Mazo ◽  
Harry Leung ◽  
Katharina Engelke ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Shape Change ◽  
Proteolytic Degradation ◽  
Amoeboid Movement ◽  
Tumor Cell Migration ◽  
Tumor Dissemination ◽  
Β1 Integrins

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

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