Tumor Cell Invasion in Glioblastoma

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

PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1500722112 ◽

2015 ◽

Vol 112 (28) ◽

pp. 8638-8643 ◽

Cited By ~ 109

Author(s):

M. Cecilia Caino ◽

Jagadish C. Ghosh ◽

Young Chan Chae ◽

Valentina Vaira ◽

Dayana B. Rivadeneira ◽

...

Keyword(s):

Tumor Cell ◽

Cell Motility ◽

Cell Invasion ◽

Mammalian Target Of Rapamycin ◽

Membrane Dynamics ◽

Tumor Cell Invasion ◽

Transcriptional Reprogramming ◽

Tumor Cell Motility ◽

Molecular Therapies ◽

Mitochondrial Trafficking

Molecular therapies are hallmarks of “personalized” medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, “spatiotemporal” mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.

Download Full-text

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

10.1101/2021.05.15.444295 ◽

2021 ◽

Author(s):

Hongjiang Si ◽

Na Zhao ◽

Andrea Pedroza ◽

Chad J. Creighton ◽

Kevin Roarty

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Surrounding Tissue ◽

Cell Matrix ◽

Integrin Α5 ◽

Ecm Architecture ◽

Tumor Organoids

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

CUTL1–a modulator of tumor cell invasion and target of TGF-beta which is highly expressed in colon cancer

Zeitschrift für Gastroenterologie ◽

10.1055/s-2004-831432 ◽

2004 ◽

Vol 42 (08) ◽

Author(s):

P Michl ◽

M Ei'Bahrawy ◽

R Poulsom ◽

A Ramjaun ◽

J Downward

Keyword(s):

Colon Cancer ◽

Tumor Cell ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Tgf Beta

Download Full-text

Faculty Opinions recommendation of Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014212.194313 ◽

2003 ◽

Author(s):

Valeri Vasioukhin

Keyword(s):

Tumor Cell ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Independent Mechanism ◽

E Cadherin

Download Full-text

Faculty Opinions recommendation of Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014212.194103 ◽

2003 ◽

Author(s):

Anna Huttenlocher

Keyword(s):

Tumor Cell ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Independent Mechanism ◽

E Cadherin

Download Full-text

Tumor Cell Invasion Assay

BIO-PROTOCOL ◽

10.21769/bioprotoc.101 ◽

2012 ◽

Vol 2 (3) ◽

Author(s):

Yanling Chen

Keyword(s):

Tumor Cell ◽

Cell Invasion ◽

Tumor Cell Invasion ◽

Invasion Assay

Download Full-text

Regulation of CD44 Alternative Splicing by SRm160 and Its Potential Role in Tumor Cell Invasion

Molecular and Cellular Biology ◽

10.1128/mcb.26.1.362-370.2006 ◽

2006 ◽

Vol 26 (1) ◽

pp. 362-370 ◽

Cited By ~ 134

Author(s):

Chonghui Cheng ◽

Phillip A. Sharp

Keyword(s):

Alternative Splicing ◽

Tumor Cell ◽

Cell Invasion ◽

Rna Splicing ◽

Tumor Cell Invasion ◽

Dependent Manner ◽

Cd44 Isoforms ◽

Transmembrane Glycoprotein ◽

Cell Invasiveness ◽

Interfering Rna

ABSTRACT The multiple isoforms of the transmembrane glycoprotein CD44 are produced by alternative RNA splicing. Expression of CD44 isoforms containing variable 5 exon (v5) correlates with enhanced malignancy and invasiveness of some tumors. Here we demonstrate that SRm160, a splicing coactivator, regulates CD44 alternative splicing in a Ras-dependent manner. Overexpression of SRm160 stimulates inclusion of CD44 v5 when Ras is activated. Conversely, small interfering RNA (siRNA)-mediated silencing of SRm160 significantly reduces v5 inclusion. Immunoprecipitation shows association of SRm160 with Sam68, a protein that also stimulates v5 inclusion in a Ras-dependent manner, suggesting that these two proteins interact to regulate CD44 splicing. Importantly, siRNA-mediated depletion of CD44 v5 decreases tumor cell invasion. Reduction of SRm160 by siRNA transfection downregulates the endogenous levels of CD44 isoforms, including v5, and correlates with a decrease in tumor cell invasiveness.

Download Full-text