Matrix Rigidity Controls Epithelial-Mesenchymal Plasticity and Tumor Metastasis via a Mechanoresponsive EPHA2/LYN Complex

Fattet, Laurent; Jung, Hae-Yun; Matsumoto, Mike W.; Aubol, Brandon E.; Kumar, Aditya; Adams, Joseph A.; Chen, Albert C.; Sah, Robert L.; Engler, Adam J.; Pasquale, Elena B.; Yang, Jing

doi:10.1016/j.devcel.2020.05.031

Cited by 154 publications

(149 citation statements)

References 48 publications

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“…One way to control transcription factors' activity is to regulate their entry into the nucleus. Intriguingly, in mammalian cell lines, Twist has been shown to be imported to the nucleus when cells are exposed to stiff substrates (Wei et al, 2015;Fattet et al, 2020). In this situation, EphA2 is activated in a ligandindependent manner and leads to the phosphorylation of Twist via LYN kinase.…”

Section: The Neural Crest Emt and The Onset Of Cell Motionmentioning

confidence: 99%

In vivo Neural Crest Cell Migration Is Controlled by “Mixotaxis”

Barriga

Théveneau

2020

Front. Physiol.

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Directed cell migration is essential all along an individual’s life, from embryogenesis to tissue repair and cancer metastasis. Thus, due to its biomedical relevance, directed cell migration is currently under intense research. Directed cell migration has been shown to be driven by an assortment of external biasing cues, ranging from gradients of soluble (chemotaxis) to bound (haptotaxis) molecules. In addition to molecular gradients, gradients of mechanical properties (duro/mechanotaxis), electric fields (electro/galvanotaxis) as well as iterative biases in the environment topology (ratchetaxis) have been shown to be able to direct cell migration. Since cells migrating in vivo are exposed to a challenging environment composed of a convolution of biochemical, biophysical, and topological cues, it is highly unlikely that cell migration would be guided by an individual type of “taxis.” This is especially true since numerous molecular players involved in the cellular response to these biasing cues are often recycled, serving as sensor or transducer of both biochemical and biophysical signals. In this review, we confront literature on Xenopus cephalic neural crest cells with that of other cell types to discuss the relevance of the current categorization of cell guidance strategies. Furthermore, we emphasize that while studying individual biasing signals is informative, the hard truth is that cells migrate by performing a sort of “mixotaxis,” where they integrate and coordinate multiple inputs through shared molecular effectors to ensure robustness of directed cell motion.

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Section: The Neural Crest Emt and The Onset Of Cell Motionmentioning

confidence: 99%

In vivo Neural Crest Cell Migration Is Controlled by “Mixotaxis”

Barriga

Théveneau

2020

Front. Physiol.

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“…Tumor cells do not typically exist in fluidbased environments in vivo, apart from tumor cells in the circulation or in bodily fluids like pleural effusions and malignant ascites. Suspension culture lacks the rigid physical structure of fully-embedded systems, which could modulate mechano-transduction and other signaling pathways relevant for cancer [17,41], as well as affect hypoxic gradients that could induce EMT and metabolic phenotypes relevant for cancer progression [34,40,48]. We therefore suggest using this method primarily for expansion.…”

Section: Resultsmentioning

confidence: 99%

Optimal, Large-Scale Propagation of Mouse Mammary Tumor Organoids

Wrenn

Moore

Greenwood

et al. 2020

J Mammary Gland Biol Neoplasia

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Tumor organoids mimic the architecture and heterogeneity of in vivo tumors and enable studies of collective interactions between tumor cells as well as with their surrounding microenvironment. Although tumor organoids hold significant promise as cancer models, they are also more costly and labor-intensive to cultivate than traditional 2D cell culture. We sought to identify critical factors regulating organoid growth ex vivo, and to use these observations to develop a more efficient organoid expansion method. Using time-lapse imaging of mouse mammary tumor organoids in 3D culture, we observed that outgrowth potential varies nonlinearly with initial organoid size. Maximal outgrowth occurred in organoids with a starting size between~10 to 1000 cells. Based on these observations, we developed a suspension culture method that maintains organoids in the ideal size range, enabling expansion from 1 million to over 100 million cells in less than 2 weeks and less than 3 hours of hands-on time. Our method facilitates the rapid, cost-effective expansion of organoids for CRISPR based studies and other assays requiring a large amount of organoid starting material.

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“…Although little is known about the role of EPHA7 in cervical cancer pathogenesis, its frequent downregulation brought about by various epigenetic mechanisms and coupled with tumor progression was determined in other epithelial malignancies, as, for example, in prostate cancer [92], colorectal cancer [93], and esophageal squamous cell carcinoma [94]. Given that the ephrin receptors are the largest known subfamily of receptor tyrosine kinases with diverse functions and modalities of action, including ligand-independent activities (such as, for example, mechanoresponsive signaling) [53,95], identification of the two members of this family among the significant genes differently expressed at the onset of invasive cervical cancer progression seems to be an important result that requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Members of the endothelin system in the "Renin secretion" pathway (EDN and EDNRA) are intrinsically implicated in angiogenesis, lymphangiogenesis, and vascular functions. All identified components of the "Axon guidance" pathway are known to act as crucial cytoskeletal remodelers; sensors of the ECM mechanic properties; and regulators, either positive or negative, of directed cell migration [53], representing a functional bridge between inflammation, angiogenesis, EMT, and invasion. For instance, members of the ephrin receptor (EPH) family have been shown to mediate crosstalk between TNFα-and TGFβ-signaling pathways [54].…”

Section: Pathway Analysismentioning

confidence: 99%

Markers of Angiogenesis, Lymphangiogenesis, and Epithelial–Mesenchymal Transition (Plasticity) in CIN and Early Invasive Carcinoma of the Cervix: Exploring Putative Molecular Mechanisms Involved in Early Tumor Invasion

Kurmyshkina

Ковчур

Schegoleva

et al. 2020

IJMS

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The establishment of a proangiogenic phenotype and epithelial-to-mesenchymal transition (EMT) are considered as critical events that promote the induction of invasive growth in epithelial tumors, and stimulation of lymphangiogenesis is believed to confer the capacity for early dissemination to cancer cells. Recent research has revealed substantial interdependence between these processes at the molecular level as they rely on common signaling networks. Of great interest are the molecular mechanisms of (lymph-)angiogenesis and EMT associated with the earliest stages of transition from intraepithelial development to invasive growth, as they could provide the source of potentially valuable tools for targeting tumor metastasis. However, in the case of early-stage cervical cancer, the players of (lymph-)angiogenesis and EMT processes still remain substantially uncharacterized. In this study, we used RNA sequencing to compare transcriptomes of HPV(+) preinvasive neoplastic lesions and early-stage invasive carcinoma of the cervix and to identify (lymph-)angiogenesis- and EMT-related genes and pathways that may underlie early acquisition of invasive phenotype and metastatic properties by cervical cancer cells. Second, we applied flow cytometric analysis to evaluate the expression of three key lymphangiogenesis/EMT markers (VEGFR3, MET, and SLUG) in epithelial cells derived from enzymatically treated tissue specimens. Overall, among 201 differentially expressed genes, a considerable number of (lymph-)angiogenesis and EMT regulatory factors were identified, including genes encoding cytokines, growth factor receptors, transcription factors, and adhesion molecules. Pathway analysis confirmed enrichment for angiogenesis, epithelial differentiation, and cell guidance pathways at transition from intraepithelial neoplasia to invasive carcinoma and suggested immune-regulatory/inflammatory pathways to be implicated in initiation of invasive growth of cervical cancer. Flow cytometry showed cell phenotype-specific expression pattern for VEGFR3, MET, and SLUG and revealed correlation with the amount of tumor-infiltrating lymphocytes at the early stages of cervical cancer progression. Taken together, these results extend our understanding of driving forces of angiogenesis and metastasis in HPV-associated cervical cancer and may be useful for developing new treatments.

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Matrix Rigidity Controls Epithelial-Mesenchymal Plasticity and Tumor Metastasis via a Mechanoresponsive EPHA2/LYN Complex

Cited by 154 publications

References 48 publications

In vivo Neural Crest Cell Migration Is Controlled by “Mixotaxis”

In vivo Neural Crest Cell Migration Is Controlled by “Mixotaxis”

Optimal, Large-Scale Propagation of Mouse Mammary Tumor Organoids

Markers of Angiogenesis, Lymphangiogenesis, and Epithelial–Mesenchymal Transition (Plasticity) in CIN and Early Invasive Carcinoma of the Cervix: Exploring Putative Molecular Mechanisms Involved in Early Tumor Invasion

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