Physical defects in basement membrane-mimicking collagen-IV matrices trigger cellular EMT and invasion

Walter, Christopher; Davis, Joshua; Mathur, Jairaj; Pathak, Amit

doi:10.1039/c8ib00034d

Cited by 24 publications

(23 citation statements)

References 64 publications

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“…On stiff gels, the vimentin expression increased, and membrane localization of E-cad decreased (Fig. 5C,F,G), both of which are consistent with the stiffness-dependent EMT observed previously (Brown et al, 2013;Nasrollahi and Pathak, 2016;Pathak, 2016;Walter et al, 2018;Wei et al, 2015). On soft gels, longer collagen fibers promoted vimentin expression ( Fig.…”

Section: Upregulated Mechanosensing Markers In Cell Streamssupporting

confidence: 90%

Longer collagen fibers trigger multicellular streaming on soft substrates via enhanced forces and cell–cell cooperation

Sarker

Bagchi

Walter

et al. 2019

Journal of Cell Science

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Grouped cells often leave large cell colonies in the form of narrow multicellular streams. However, it remains unknown how collective cell streaming exploits specific matrix properties, like stiffness and fiber length. It is also unclear how cellular forces, cell-cell adhesion and velocities are coordinated within streams. To independently tune stiffness and collagen fiber length, we developed new hydrogels and discovered invasion-like streaming of normal epithelial cells on soft substrates coated with long collagen fibers. Here, streams arise owing to a surge in cell velocities, forces, YAP activity and expression of mesenchymal marker proteins in regions of high-stress anisotropy. Coordinated velocities and symmetric distribution of tensile and compressive stresses support persistent stream growth. Stiff matrices diminish cell-cell adhesions, disrupt front-rear velocity coordination and do not promote sustained fiber-dependent streaming. Rac inhibition reduces cell elongation and cell-cell cooperation, resulting in a complete loss of streaming in all matrix conditions. Our results reveal a stiffness-modulated effect of collagen fiber length on collective cell streaming and unveil a biophysical mechanism of streaming governed by a delicate balance of enhanced forces, monolayer cohesion and cell-cell cooperation.

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Section: Upregulated Mechanosensing Markers In Cell Streamssupporting

confidence: 90%

Longer collagen fibers trigger multicellular streaming on soft substrates via enhanced forces and cell–cell cooperation

Sarker

Bagchi

Walter

et al. 2019

Journal of Cell Science

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“…A hallmark of EMT is the loss of epithelial polarization, which by itself is linked to anchorage of epithelial layers on a basement membrane (BM). Walter et al found that defects in the BM and of Col IV deposition in particular can trigger EMT (Walter et al, 2018). In proximal tubular epithelial cells, Col IV helps to maintain an epithelial phenotype, while Col I promotes EMT (Zeisberg et al, 2001).…”

Section: The Ecm Regulates Emt and Metastasismentioning

confidence: 99%

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Henke

Nandigama

Ergün

2020

Front. Mol. Biosci.

771

613

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Solid tumors are complex organ-like structures that consist not only of tumor cells but also of vasculature, extracellular matrix (ECM), stromal, and immune cells. Often, this tumor microenvironment (TME) comprises the larger part of the overall tumor mass. Like the other components of the TME, the ECM in solid tumors differs significantly from that in normal organs. Intratumoral signaling, transport mechanisms, metabolisms, oxygenation, and immunogenicity are strongly affected if not controlled by the ECM. Exerting this regulatory control, the ECM does not only influence malignancy and growth of the tumor but also its response toward therapy. Understanding the particularities of the ECM in solid tumor is necessary to develop approaches to interfere with its negative effect. In this review, we will also highlight the current understanding of the physical, cellular, and molecular mechanisms by which the pathological tumor ECM affects the efficiency of radio-, chemo-, and immunotherapy. Finally, we will discuss the various strategies to target and modify the tumor ECM and how they could be utilized to improve response to therapy.

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“…The increased motility/invasiveness associated with the mesenchymal cell state has linked the EMT program with metastasis, in which cell separation from the primary tumor mass can be considered as the rst step of the invasion-metastasis cascade. Thus, a variety of studies have demonstrated that induction of an EMT program allows carcinoma cells to lose cell-cell junctions, degrade local basement membrane via elevated expression of various matrixdegrading enzymes, and thus support their migration and invasion [21][22][23][24]. Therefore, SIPA1L3 overexpression promotes malignant lung cell growth, invasion, and EMT, which may explain our ndings that SIPA1L3 overexpression was the major de ning characteristic of NSCLC tumors and correlated with several clinicopathological factors.…”

Section: Discussionmentioning

confidence: 59%

Knockdown of SIPA1L3 Inhibits the Proliferation and Invasion of Non–Small Cell Lung Cancer Cells Through the Hippo Pathway

Wang¹,

Han²,

Rong³

et al. 2021

Preprint

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Background: SIPA1L3 is a member of the signal-induced proliferation-associated (SIPA) protein family, only limited data about the SIPA1L3 are currently available in human carcinoma. Our present study provides the expression pattern and function of SIPA1L3 in non-small cell lung cancer (NSCLC).Methods: We performed immunohistochemistry to detect the distribution of SIPA1L3 in NSCLC specimens and analyzed the relationship between SIPA1L3 expression and patients clinicopathological feature. We used small interfering RNA (siRNA) to specifically silence SIPA1L3, then investigated its effect on cell growth and invasion in human lung cancer cell lines. Western blot and immunoprecipitation were performed to show the interaction of SIPA1L3 with the core proteins of Hippo pathway, and the Hippo pathway activity.Results: Immunohistochemical staining showed that SIPA1L3 was cytoplasmic increasing in 147 of 217 cases. High levels of SIPA1L3 expression were associated with poor differentiation and a high tumor node metastasis stage, positive lymph nodal status, and poor prognosis. Downregulation of SIPA1L3 inhibited cell EMT, growth, and invasion. As well as SIPA1L3 inhibited Hippo pathway. SIPA1L3 interacted with AMOT, which inhibited AMOT binding to Pals, then decreased nuclear location of YAP.Conclusions: SIPA1L3 overexpression may be a marker for advanced NSCLC. SIPA1L3 reduction inhibits the proliferative and invasive ability of the lung cancer cells, which involves the Hippo pathway by contacting with AMOT.

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Physical defects in basement membrane-mimicking collagen-IV matrices trigger cellular EMT and invasion

Cited by 24 publications

References 64 publications

Longer collagen fibers trigger multicellular streaming on soft substrates via enhanced forces and cell–cell cooperation

Longer collagen fibers trigger multicellular streaming on soft substrates via enhanced forces and cell–cell cooperation

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

Knockdown of SIPA1L3 Inhibits the Proliferation and Invasion of Non–Small Cell Lung Cancer Cells Through the Hippo Pathway

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