Ultraviolet light-induced collagen degradation inhibits melanoma invasion

AbstractUltraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

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Ultraviolet light-induced collagen degradation inhibits melanoma invasion

10.1101/2021.01.27.428482 ◽

2021 ◽

Author(s):

Timothy Budden ◽

Caroline Gaudy ◽

Andrew Porter ◽

Emily Kay ◽

Shilpa Gurung ◽

...

Keyword(s):

Cell Invasion ◽

Older Patients ◽

Dermal Fibroblast ◽

Single Cells ◽

Primary Melanoma ◽

The Elderly ◽

Invasive Front ◽

Melanoma Invasion ◽

Local Levels

AbstractUltraviolet radiation (UVR) increases the incidence of cutaneous melanoma1–4. The ageing, sun-exposed dermis accumulates UVR damage5, and older patients develop more melanomas at UVR-exposed sites4,6,7. As fibroblasts are functionally heterogeneous and play key roles in the stromal contribution to cancer8,9, we asked whether UVR modifies dermal fibroblast function. Here we confirmed the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) by UVR-damaged fibroblasts was persistently upregulated to reduce local levels of collagen 1 (COL1A1), and found dermal COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, we show inhibiting extracellular matrix degradation and MMP1 expression restored melanoma invasion to UVR damaged dermis. We confirmed in vitro findings in a cohort of primary cutaneous melanomas of aged humans, showing more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen. We found collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. These data indicate melanomas arising over UVR-damaged, collagen-poor skin of the elderly are less invasive, and this reduced invasion improves survival. Consequently, although UVR increases tumour incidence, it delays primary melanoma invasion by degrading collagen. However, we show melanoma-associated fibroblasts can restore invasion in low-collagen primary tumours by increasing collagen synthesis. Finally, we demonstrate high COL1A1 gene expression is a biomarker of poor outcome across a broad range of primary cancers.

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STIM1- and Orai1-mediated Ca2+ oscillation orchestrates invadopodium formation and melanoma invasion

The Journal of Cell Biology ◽

10.1083/jcb.201407082 ◽

2014 ◽

Vol 207 (4) ◽

pp. 535-548 ◽

Cited By ~ 81

Author(s):

Jianwei Sun ◽

Fujian Lu ◽

Huifang He ◽

Junling Shen ◽

Jane Messina ◽

...

Keyword(s):

Extracellular Matrix ◽

Plasma Membrane ◽

Mouse Model ◽

Matrix Metalloproteinase ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

Melanoma Invasion ◽

Ecm Degradation ◽

Underlying Mechanisms

Ca2+ signaling has been increasingly implicated in cancer invasion and metastasis, and yet, the underlying mechanisms remained largely unknown. In this paper, we report that STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation. Ca2+ oscillation signals facilitate invadopodial precursor assembly by activating Src. Disruption of Ca2+ oscillations inhibited invadopodium assembly. Furthermore, STIM1 and Orai1 regulate the proteolysis activity of individual invadopodia. Mechanistically, Orai1 blockade inhibited the recycling of MT1–matrix metalloproteinase (MMP) to the plasma membrane and entrapped MT1-MMP in the endocytic compartment to inhibit ECM degradation. STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft mouse model, implicating the importance of this pathway in metastatic dissemination. Our findings provide a novel mechanism for Ca2+-mediated cancer cell invasion and shed new light on the spatiotemporal organization of store-operated Ca2+ signals during melanoma invasion and metastasis.

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Regulation of Gene Expression in Endometrial Cancer Cells: Role of Extracellular Matrix in Mitochondrial Gene Expression

Cell and Molecular Biology of Endometrial Carcinoma ◽

10.1007/978-4-431-53981-0_15 ◽

2003 ◽

pp. 221-231

Author(s):

Elisabeth Strunck ◽

Kirsten Frank ◽

Günter Vollmer

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Endometrial Cancer ◽

Cancer Cells ◽

Mitochondrial Gene ◽

Regulation Of Gene Expression ◽

Mitochondrial Gene Expression

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Dynamics of 3D carcinoma cell invasion into aligned collagen

Integrative Biology ◽

10.1039/c7ib00152e ◽

2018 ◽

Vol 10 (2) ◽

pp. 100-112 ◽

Cited By ~ 12

Author(s):

Arja Ray ◽

Rachel K. Morford ◽

Nima Ghaderi ◽

David J. Odde ◽

Paolo. P. Provenzano

Keyword(s):

Extracellular Matrix ◽

Cancer Cell ◽

Cell Invasion ◽

Carcinoma Cell ◽

Spatiotemporal Dynamics ◽

Contact Inhibition ◽

Contact Guidance ◽

Cell Behavior ◽

Cancer Cell Invasion ◽

Invasive Front

We present a novel platform to quantify spatiotemporal dynamics of cell behavior at and beyond the invasive front and demonstrate that contact inhibition and contact guidance orchestrate cancer cell invasion into anisotropic extracellular matrix.

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The Role of Structural Extracellular Matrix Proteins in Urothelial Bladder Cancer (Review)

Biomarker Insights ◽

10.4137/bmi.s294 ◽

2007 ◽

Vol 2 ◽

pp. BMI.S294 ◽

Cited By ~ 14

Author(s):

Andrea Brunner ◽

Alexandar Tzankov

Keyword(s):

Extracellular Matrix ◽

Cancer Cells ◽

Cell Invasion ◽

Matrix Proteins ◽

Urothelial Bladder Cancer ◽

Ecm Proteins ◽

Cancer Review ◽

Urothelial Bladder ◽

Carcinoma Of The Bladder

The extracellular matrix (ECM) plays a key role in the modulation of cancer cell invasion. In urothelial carcinoma of the bladder (UC) the role of ECM proteins has been widely studied. The mechanisms, which are involved in the development of invasion, progression and generalization, are complex, depending on the interaction of ECM proteins with each other as well as with cancer cells. The following review will focus on the pathogenetic role and prognostic value of structural proteins, such as laminins, collagens, fibronectin (FN), tenascin (Tn-C) and thrombospondin 1 (TSP1) in UC. In addition the role of integrins mediating the interaction of ECM molecules and cancer cells will be addressed, since integrin-mediated FN, Tn-C and TSP1 interactions seem to play an important role during tumor cell invasion and angiogenesis.

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Curcumin Down-Regulates Visfatin Expression and Inhibits Breast Cancer Cell Invasion

Endocrinology ◽

10.1210/en.2011-1413 ◽

2012 ◽

Vol 153 (2) ◽

pp. 554-563 ◽

Cited By ~ 32

Author(s):

Su-Ryun Kim ◽

Hyun-Joo Park ◽

Yun-Hee Bae ◽

Soon-Cheol Ahn ◽

Hee-Jun Wee ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Breast Cancer Cell ◽

Cell Invasion ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Human Breast Cancer Cells ◽

Cancer Cell Invasion ◽

Human Breast

Obesity is frequently associated with breast cancer. Such associations are possibly mediated by adipokines. Visfatin, an adipokine, has recently been shown to be related to the development and progression of breast cancer. Therefore, the down-regulation of visfatin may be a novel strategy for breast cancer therapy. Curcumin has anticancer activities by modulating multiple signaling pathways and genes. The purpose of this study was to investigate whether visfatin gene expression is affected by curcumin in human breast cancer cells and to characterize the functional role of visfatin in breast cancer. We found that the mRNA and protein levels of visfatin were down-regulated by curcumin in MDA-MB-231, MDA-MB-468, and MCF-7 breast cancer cells, along with decreased activity of constitutive nuclear factor (NF)-κB. We confirmed the repressive effect of curcumin on visfatin transcription by performing a visfatin promoter-driven reporter assay and identified two putative NF-κB-binding sites on visfatin promoter that are important for this effect. EMSA and chromatin immunoprecipitation analysis indicated the binding of p65 to the visfatin promoter, which was effectively blocked by curcumin. Enforced expression of p65 protein increased visfatin promoter activity, whereas blocking NF-κB signaling suppressed visfatin gene expression. Visfatin could enhance the invasion of MDA-MB-231 cells and also attenuate curcumin-induced inhibition of cell invasion; on the other hand, visfatin knockdown by small interfering RNA led to the reduction of cell invasion. Our data demonstrate, for the first time, that curcumin down-regulates visfatin gene expression in human breast cancer cells by a mechanism that is, at least in part, NF-κB dependent and suggest that visfatin may contribute to breast cancer cell invasion and link obesity to breast cancer development and progression.

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Sterculic Acid Alters Adhesion Molecules Expression and Extracellular Matrix Compounds to Regulate Migration of Lung Cancer Cells

Cancers ◽

10.3390/cancers13174370 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4370

Author(s):

Rafael Pelaez ◽

Rodrigo Ochoa ◽

Ana Pariente ◽

Angela Villanueva-Martínez ◽

Álvaro Pérez-Sala ◽

...

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Cancer Cells ◽

Adhesion Molecules ◽

Epithelial To Mesenchymal Transition ◽

Sterculic Acid ◽

Main Function ◽

Cyclopropenoid Fatty Acid ◽

Mesenchymal Transition ◽

Migration Capacity

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies many other pathways and the underlying gene expression. SCD overexpression, or up-regulated activity, has been associated with tumor aggressiveness and poor prognosis in many cancer types. Scd1 down-regulation, with different inhibitors or molecular strategies, reduces tumor cell survival and cell proliferation, as well as the chemoresistance associated with cancer stem cell presence. However, SA effects over cancer cell migration and extracellular matrix or adhesion molecules have not been described in cancer cells up to now. We used different migration assays and qPCR gene expression analysis to evaluate the effects of SA treatment in cancer cells. The results reveal that SA induces tumoral cell death at high doses, but we also observed that lower SA-treatments induce cell adhesion-migration capacity reduction as a result of modifications in the expression of genes related to integrins and extracellular matrix compounds. Overall, the functional and transcriptomic findings suggest that SA could represent a new inhibitor activity of epithelial to mesenchymal transition.

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ID: 1027 High-Throughput, Single Cell Whole Transcriptome Sequencing Analysis of Cancer Cells with the New BD FACSMelody™ Cell Sorter and BD™ Precise assay

Biomedical Research and Therapy ◽

10.15419/bmrat.v4is.303 ◽

2017 ◽

Vol 4 (S) ◽

pp. 102

Author(s):

Xiaoyang (Alice) Wang ◽

Chip Lomas ◽

Craig Betts ◽

Aaron Walker ◽

Christina Fan ◽

...

Keyword(s):

Gene Expression ◽

Single Cell ◽

Cancer Cells ◽

Cell Line ◽

Selection Criteria ◽

Single Cells ◽

Principal Component ◽

Jurkat Cells ◽

Sequencing Analysis ◽

Whole Transcriptome

Gene expression studies performed on bulk samples might obscure the understanding of complex samples. Gene expression analyses performed on single cells, however, can offer a powerful method to resolve sample heterogeneity and reveal hidden biology. Optimal sample preparation is critical to obtain high quality gene expression data from single cells.Historically, single cells or small numbers of cells were isolated and prepared by limiting dilutions, laser capture microdissection, or microfluidics technologies, or fluorescence-activated cell sorting (FACS). FACS sorting enables highthroughput processing of a heterogeneous mixture of cells and ensures the delivery of single cells or a small number ofcells into a chosen receptacle to meet the selection criteria at a purity level that is unmatched by other approaches.Furthermore, by FACS, the single cell selection criteria can be based on surface marker expression, cell size, and granularity(represented by scatter). Sorted cells can be used for any downstream application including next generation sequencing(NGS).In this study, the new, easy-to-use BD FACSMelody™ sorter was applied to sort individual cancer cells. Jurkat cells (a Tleukemia cell line), and T47D cells (a breast cancer cell line) were mixed, stained, analyzed, and sorted on a BD FACSMelody system. The individual cell’s whole transcriptome was interrogated using BD™ Precise Single Cell WTA (whole transcriptome amplification) Assay. Principal component analysis was applied to cluster the sorted Jurkat and T47D-cell populations.

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Comparative use of CRISPR and RNAi to modulate integrin α3β1 in triple negative breast cancer cells reveals that some pro-invasive/pro-metastatic α3β1 functions are independent of global regulation of the transcriptome

PLoS ONE ◽

10.1371/journal.pone.0254714 ◽

2021 ◽

Vol 16 (7) ◽

pp. e0254714

Author(s):

James Kenney ◽

Abibatou Ndoye ◽

John M. Lamar ◽

C. Michael DiPersio

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Tumor Growth ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Cell Invasion ◽

Triple Negative ◽

Rnai Technology ◽

Integrin Α3β1

Integrin receptors for the extracellular matrix play critical roles at all stages of carcinogenesis, including tumor growth, tumor progression and metastasis. The laminin-binding integrin α3β1 is expressed in all epithelial tissues where it has important roles in cell survival, migration, proliferation, and gene expression programs during normal and pathological tissue remodeling. α3β1 signaling and adhesion functions promote tumor growth and metastasis in a number of different types of cancer cells. Previously, we used RNA interference (RNAi) technology to suppress the expression of the ITGA3 gene (encoding the α3 subunit) in the triple-negative breast cancer cell line, MDA-MB-231, thereby generating variants of this line with reduced expression of integrin α3β1. This approach revealed that α3β1 promotes pro-tumorigenic functions such as cell invasion, lung metastasis, and gene regulation. In the current study, we used CRISPR technology to knock out the ITGA3 gene in MDA-MB-231 cells, thereby ablating expression of integrin α3β1 entirely. RNA-seq analysis revealed that while the global transcriptome was altered substantially by RNAi-mediated suppression of α3β1, it was largely unaffected following CRISPR-mediated ablation of α3β1. Moreover, restoring α3β1 to the latter cells through inducible expression of α3 cDNA failed to alter gene expression substantially, suggesting that use of CRISPR to abolish α3β1 led to a decoupling of the integrin from its ability to regulate the transcriptome. Interestingly, both cell invasion in vitro and metastatic colonization in vivo were reduced when α3β1 was abolished using CRISPR, as we observed previously using RNAi to suppress α3β1. Taken together, our results show that pro-invasive/pro-metastatic roles for α3β1 are not dependent on its ability to regulate the transcriptome. Moreover, our finding that use of RNAi versus CRISPR to target α3β1 produced distinct effects on gene expression underlines the importance of using multiple approaches to obtain a complete picture of an integrin’s functions in cancer cells.

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