Non-canonical Wnt/Ror2 signaling status regulates cell-matrix crosstalk to prompt directional tumor cell invasion and dissemination in breast cancer

Cancer deaths largely result from metastasis, the spread of cancer from the primary tumor to distant organs. Initial steps of metastasis require that tumor cells invade into the surrounding tissue and gain access to blood or lymphatic vessels. Such invasion is reliant on a balance of cell-cell and cell-matrix cues within the microenvironment of the tumor, yet factors regulating such interactions for invading tumor cells remain elusive in the context of cancer. We demonstrate that the noncanonical Wnt receptor, Ror2, in mammary tumor models of Tripe Negative Breast Cancer, regulates the composition and remodeling of the tumor stroma, where Ror2-depletion prompts directional tumor cell invasion and coordinated ECM production at the leading edge of tumor cell movement. By RNA sequencing, we discovered that tumor organoids specifically harbor actin cytoskeleton, cell adhesion, and collagen cross-linking gene expression programs when Wnt/Ror2 signaling is impaired. Interestingly, Ror2 depletion resulted in the downregulation of E-cadherin in tumor organoids, particularly at invading tumor cell protrusions within the surrounding ECM. Spatially, we identified the upregulation and redistribution of integrin receptors, particularly integrin-α5 in Ror2-deficient tumor organoids, accompanied by the simultaneous production of a provisional Fibronectin matrix, a requisite component of the ECM, ligand for integrin α5, and mediator of collagen assembly and organization. Along with altered ECM architecture, Ror2 loss reshaped the topology of integrin and FAK activation within primary tumors, suggesting an important physiological function for Ror2 in shaping both signaling and ECM architecture during tumor progression. Blocking either integrin or FAK, a downstream mediator of integrin-mediated signal transduction, abrogated the enhanced migration observed upon Ror2 loss. These results suggest that Ror2 status within a tumor can significantly impact adhesive vs. migratory states in breast cancer and provide a novel mechanism where Wnt/Ror2 shapes not only tumor cell composition, but also reciprocal cell-ECM interactions prompting directional and collaborative tumor cell transit during cancer progression.

Download Full-text

Morphological features of invasion of tumor cells of invasive ductal breast cancer

Morphologia ◽

10.26641/1997-9665.2021.3.119-124 ◽

2021 ◽

Vol 15 (3) ◽

pp. 119-124

Author(s):

L.A. Naleskina ◽

T.V. Zadvornyi ◽

L.M. Kunska ◽

N.Y. Lukianova

Keyword(s):

Breast Cancer ◽

Connective Tissue ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Invasive Front ◽

Invasive Ductal Breast Cancer ◽

Pathological Characteristics ◽

Ductal Breast Cancer

Background. Nowadays, it has been proven that along with the invasion of individual tumor cells, their group migration occurs in the invasive front of the tumor, and this is an important factor in tumor progression. Objective: to determine the features of tumor cell invasion in the invasive front (IF) of invasive ductal breast cancer (BCa) without special specific features (IC NST) and to establish associative links between them and the clinical and pathological characteristics of the disease. Methods. The study was performed on BCa samples (after hematoxylin and eosin stained) from 120 patients with invasive ductal BCa I-II stage with G2 grade of tumor differentiation that didn’t receive neoadjuvant chemotherapy. Results. Tumors were divided into 3 groups: with predominance of parenchymal component (PC), with the larger component of connective tissue, and relatively equivalent ratio of these components. Within the IF of the studied tumors of patients with ІІ stage of the tumor process, group invasion of tumor structures was mainly determined, both separately and in combination. In particular, an increase in solid structures in tumors with a predominance of the PC, and in neoplasms with expressed desmoplastic changes in connective tissue and their advantage, - alveolar, tubular, discrete. Conclusion. In tumors of patients with invasive ductal BCa in the invasive front is dominated by collective migration of tumor cells, which is the starting mechanism of tumor progression and the first step of the metastatic process. Defined associative links between the features of tumor cell invasion and the clinical and pathological characteristics of the tumor process in BCa patients can be used in predicting this form of cancer.

Download Full-text

Pathological Investigation of Meningioma Capsule with respect to Tumor Cell Invasion

10.21203/rs.3.rs-945497/v1 ◽

2021 ◽

Author(s):

Takashi Sugawara ◽

Daisuke Kobayashi ◽

Taketoshi Maehara

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Cell Invasion ◽

Tumor Invasion ◽

Recurrence Risk ◽

Tumor Cell Invasion ◽

Brain Surface ◽

Eloquent Cortex ◽

The Brain

Abstract OBJECTIVE No previous study has pathologically investigated whether the meningioma capsule presents with tumor cells. We investigated which types of tumor capsules include tumor cells to help decide the kind of capsules which can be left intraoperatively without recurrence risk. METHODS We investigated 22 specimens of 14 newly diagnosed meningiomas between February 2011 and June 2021. Capsules were classified into three types: tumor capsule (TC), capsule-like thickened arachnoid membrane (CAM), and extended membrane (EM). Capsule properties were scored as hardness (soft = 1, medium = 2, hard = 3) and transparency (high = 1, medium = 2, low = 3). Hardness, transparency, and score sum was compared between capsules with/without tumor invasion in CAM and EM types. RESULTS The mean follow-up duration was 28.1 months, and there was only one recurrence in a remote location from the residual capsule. Nine capsules were classified as TC, seven as CAM, and six as EM. 88.9% of TCs, 42.9% of CAMs, and 50% of EMs were invaded by tumor cells. Hardness, transparency, and score sum in CAM with tumor invasion was lower than in CAM without, but not significant (p = 0.114, p = 0.114, p = 0.057). CONCLUSION Thickened TC or soft and highly transparent CAM imply a high risk of tumor cell invasion, thus such cases should be followed up long and carefully. The hard and low transparent residual CAMs may have low risk of tumor invasion, thus these kinds of residual capsules might not increase the recurrence risk. Thus, leaving such capsules tightly adhered to the eloquent cortex is theoretically justified to avoid damaging the brain surface.

Download Full-text

Tumor Cell Invasion in Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms21061932 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1932 ◽

Cited By ~ 6

Author(s):

Arabel Vollmann-Zwerenz ◽

Verena Leidgens ◽

Giancarlo Feliciello ◽

Christoph A. Klein ◽

Peter Hau

Keyword(s):

Tumor Cell ◽

Cell Invasion ◽

Treatment Resistance ◽

Tumor Cell Invasion ◽

Surrounding Tissue ◽

Glioma Invasion ◽

Curative Therapy ◽

New Therapeutic Approaches ◽

Invasion Mechanisms ◽

Tumor Cell Motility

Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.

Download Full-text

Aspirin inhibits platelets from reprogramming breast tumor cells and promoting metastasis

Blood Advances ◽

10.1182/bloodadvances.2018026161 ◽

2019 ◽

Vol 3 (2) ◽

pp. 198-211 ◽

Cited By ~ 11

Author(s):

Kelly E. Johnson ◽

Julia R. Ceglowski ◽

Harvey G. Roweth ◽

Jodi A. Forward ◽

Mason D. Tippy ◽

...

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Cell Invasion ◽

Breast Tumor ◽

Tumor Metastasis ◽

Tumor Cell Invasion ◽

Akt Pathway ◽

Breast Tumor Cells ◽

Invasive Capacity ◽

Platelet Releasate

Abstract It is now recognized that compounds released from tumor cells can activate platelets, causing the release of platelet-derived factors into the tumor microenvironment. Several of these factors have been shown to directly promote neovascularization and metastasis, yet how the feedback between platelet releasate and the tumor cell affects metastatic phenotype remains largely unstudied. Here, we identify that breast tumor cells secrete high levels of interleukin 8 (IL-8, CXCL8) in response to platelet releasate, which promotes their invasive capacity. Furthermore, we found that platelets activate the Akt pathway in breast tumor cells, and inhibition of this pathway eliminated IL-8 production. We therefore hypothesized inhibiting platelets with aspirin could reverse the prometastatic effects of platelets on tumor cell signaling. Platelets treated with aspirin did not activate the Akt pathway, resulting in reduced IL-8 secretion and impaired tumor cell invasion. Of note, patients with breast cancer receiving aspirin had lower circulating IL-8, and their platelets did not increase tumor cell invasion compared with patients not receiving aspirin. Our data suggest platelets support breast tumor metastasis by inducing tumor cells to secrete IL-8. Our data further support that aspirin acts as an anticancer agent by disrupting the communication between platelets and breast tumor cells.

Download Full-text

P11.65 Insights into the mechanisms of primary brain tumor invasion

Neuro-Oncology ◽

10.1093/neuonc/noz126.211 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii58-iii59

Author(s):

A Bikfalvi ◽

T Daubon ◽

C Billottet

Keyword(s):

Extracellular Matrix ◽

Tumor Cell ◽

Tumor Cells ◽

Conformational Changes ◽

Cell Invasion ◽

Immune Cell ◽

Tumor Cell Invasion ◽

Migration And Invasion ◽

Matricellular Proteins

Abstract We have made progress in unravelling the mechanisms of tumor cell invasion by focusing the attention on two molecular pathways including chemokines and extracellular matrix molecules. Chemokines are important mediators of cell signaling that operate both on normal cells and tumor cells and in the immune-cell compartment (Billottet et al, 2013). Among the chemokine receptors, CXCR3 mediate diverse biological functions and comes in two major isoforms the A and B isoform. We found that ligand affinities and conformational changes are very different for the A and B form. We have recently elucidated the role and mechanism of CXCR3A in GBM invasion (Boyé et al, 2017b). We demonstrated that agonist stimulation enhances in vitro cell migration and invasion in GBM cells. A major finding was that CXCR3A forms a complex with the trafficking receptor Lipoprotein-related receptor-1 (LRP1). Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to sustained receptor activity and increase in the migration. This was also clinically validated. Our study defines LRP1 as a new regulator of CXCR3 and indicates that targeting CXCR3-A in GBM may constitute a promising strategy to halt tumor cell invasion. The extracellular matrix (ECM) has morphogenic roles in tumors. Important ECM components are the matricellular proteins, called thrombospondins(THBS1-5) (Adams and Lawler 2011). We recently elucidated the complex role of THSB1 in GBM invasion (Daubon et al.2019). Global expression analysis revealed that THBS1 is up-regulated in GBMs and associated with a poor prognosis. We, furthermore, demonstrated that THBS1 did not activate TGFβ in GBM but that TGFβ1 induced the expression of THBS1 via SMAD3. Furthermore, GBM invasion is compromised when THBS1 is silenced in tumor cells. Thus, our data clearly show that THBS1 is not only involved in the regulation of angiogenesis in GBM, but also impacts the invasive behaviour of glioma cells by interacting with a molecule called CD47 expressed on the surface of GBM cells. RNA-sequencing after microdissection of central and peripheral tumour areas in a human PDX model demonstrated that THBS1 was the gene with the highest connectivity in the peripheral invasive tumour areas. Taken together, these data indicate that THBS1 plays important role in the infiltrative process in GBM. REFERENCES: Adams JC, Lawler J. Cold Spring Harb Perspect Biol. 2011;3:a009712 Billottet C, Quemener C, Bikfalvi A. Biochim Biophys Acta. 2013;1836:287- Boyé K et al. Sci Rep. 2017;7:10703 Boyé K et al. Nat Commun. 2017;8:1571 Daubon T et al, Nature Communications. Nat Commun. 2019 Mar 8;10(1):1146 Murphy-Ullrich JE, Poczatek M. Cytokine Growth Factor Rev. 2000 11:59

Download Full-text

Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells

The Journal of Cell Biology ◽

10.1083/jcb.201702184 ◽

2017 ◽

Vol 217 (1) ◽

pp. 375-395 ◽

Cited By ~ 20

Author(s):

Alessandro Genna ◽

Stefanie Lapetina ◽

Nikola Lukic ◽

Shams Twafra ◽

Tomer Meirson ◽

...

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Tumor Cell ◽

Cancer Cells ◽

Focal Adhesion ◽

Cell Invasion ◽

Invasive Breast Cancer ◽

Breast Cancer Cells ◽

Tumor Cell Invasion ◽

And Function

The nonreceptor tyrosine kinase Pyk2 is highly expressed in invasive breast cancer, but the mechanism by which it potentiates tumor cell invasiveness is unclear at present. Using high-throughput protein array screening and bioinformatic analysis, we identified cortactin as a novel substrate and interactor of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 colocalizes with cortactin to invadopodia of invasive breast cancer cells, where it mediates epidermal growth factor–induced cortactin tyrosine phosphorylation both directly and indirectly via Src-mediated Abl-related gene (Arg) activation, leading to actin polymerization in invadopodia, extracellular matrix degradation, and tumor cell invasion. Both Pyk2 and the closely related focal adhesion kinase (FAK) regulate tumor cell invasion, albeit via distinct mechanisms. Although Pyk2 regulates tumor cell invasion by controlling invadopodium-mediated functions, FAK controls invasiveness of tumor cells by regulating focal adhesion–mediated motility. Collectively, our findings identify Pyk2 as a unique mediator of invadopodium formation and function and also provide a novel insight into the mechanisms by which Pyk2 mediates tumor cell invasion.

Download Full-text

JNP3, a new compound, suppresses PMA-induced tumor cell invasion via NF-κB down regulation in MCF-7 breast cancer cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.03.133 ◽

2012 ◽

Vol 421 (2) ◽

pp. 190-196 ◽

Cited By ~ 8

Author(s):

Hai Yang Yu ◽

Kyoung-Sook Kim ◽

Hyung-In Moon ◽

Kyung-Mi Kim ◽

Young-Choon Lee ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Cancer Cells ◽

Cell Invasion ◽

Breast Cancer Cells ◽

Tumor Cell Invasion ◽

Down Regulation ◽

Mcf 7

Download Full-text

Dynamin 2 interacts with α-actinin 4 to drive tumor cell invasion

Molecular Biology of the Cell ◽

10.1091/mbc.e19-07-0395 ◽

2020 ◽

Vol 31 (6) ◽

pp. 439-451 ◽

Cited By ~ 4

Author(s):

Kevin M. Burton ◽

Hong Cao ◽

Jing Chen ◽

Li Qiang ◽

Eugene W. Krueger ◽

...

Keyword(s):

Cell Migration ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Related Protein ◽

Invasive Tumor ◽

Invasive Cell ◽

Dynamin 2

Dyn2 and α-actinin 4 interact directly to regulate invasive cell migration and the stabilization of invadopodia. Intriguingly, this is specific for α-actinin 4, and not the highly related protein α-actinin 1. These findings elucidate a novel mechanism of regulating cell migration, with important implications for invasive tumor cells.

Download Full-text