Extra domain A‐containing fibronectin expression in <i>Spin90</i>‐deficient fibroblasts mediates cancer‐stroma interaction and promotes breast cancer progression

Kwon, Ahreum; Chae, In Hee; You, Eunae; Kim, Sohee; Ahn, Suyeon; Lee, Ok-Jun; Park, Chul–Seung; Rhee, Sangmyung; Huh, Yun Hyun; Song, Woo Keun

doi:10.1002/jcp.29326

Cited by 13 publications

(6 citation statements)

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“…Interestingly, another EDA binding integrin receptor, α9β1, is overexpressed in TNBC and associated with reduced overall survival and tumor invasion [5,97]. Additionally, reagents designed to disrupt integrin binding to the EDA domain of fibronectin inhibit breast cancer progression in mouse models [4]. The findings reported herein, point to the need for future studies to define the molecular basis for the cell type selection of TLR activation by tumor-derived DAMPs.…”

Section: Discussionmentioning

confidence: 76%

“…In response to paracrine signals from the tumor cells, stromal fibroblasts differentiate into highly contractile myofibroblasts. These cancer-associated fibroblasts (CAFs) assemble an extracellular matrix (ECM) enriched for the alternatively spliced isoform of fibronectin which contains an extra Type III Domain, Extra Domain A (EDA) [4,5]. Structurally, fibronectin is organized into individually folded domains, termed Types I, II, and III.…”

Section: Introductionmentioning

confidence: 99%

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Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

Ambesi

Maddali

McKeown‐Longo

2022

Cells

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The microenvironment of tumors is characterized by structural changes in the fibronectin matrix, which include increased deposition of the EDA isoform of fibronectin and the unfolding of the fibronectin Type III domains. The impact of these structural changes on tumor progression is not well understood. The fibronectin EDA (FnEDA) domain and the partially unfolded first Type III domain of fibronectin (FnIII-1c) have been identified as endogenous damage-associated molecular pattern molecules (DAMPs), which induce innate immune responses by serving as agonists for Toll-Like Receptors (TLRs). Using two triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, we show that FnEDA and FnIII-1c induce the pro-tumorigenic cytokine, IL-8, by serving as agonists for TLR5 and TLR2, the canonical receptors for bacterial flagellin and lipoprotein, respectively. We also find that FnIII-1c is not recognized by MDA-MB-468 cells but is recognized by MDA-MB-231 cells, suggesting a cell type rather than ligand specific utilization of TLRs. As IL-8 plays a major role in the progression of TNBC, these studies suggest that tumor-induced structural changes in the fibronectin matrix promote an inflammatory microenvironment conducive to metastatic progression.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

Ambesi

Maddali

McKeown‐Longo

2022

Cells

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“…We previously showed that SPIN90 depletion leads to fibroblast activation, which contributes to breast cancer tumorigenesis [ 22 , 32 , 33 ]. Thus, we herein examined whether overexpression of the SPIN90-targeting miRNA, miR-130b-3p, could induce fibroblast activation.…”

Section: Resultsmentioning

confidence: 99%

Tumor-derived miR-130b-3p induces cancer-associated fibroblast activation by targeting SPIN90 in luminal A breast cancer

et al. 2022

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Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) interact closely with cancer cells to promote tumor development. Downregulation of SPIN90 in CAFs has been reported to facilitate breast cancer progression, but the underlying mechanism has not been elucidated. Here, we demonstrate that miR-130b-3p directly downregulates SPIN90 in stromal fibroblasts, leading to their differentiation into CAFs. As the decrease of SPIN90 in CAFs was shown to be more prominent in estrogen receptor (ER)-positive breast tumors in this study, miR-130b-3p was selected by bioinformatics analysis of data from patients with ER-positive breast cancer. Ectopic expression of miR-130b-3p in fibroblasts accelerated their differentiation to CAFs that promote cancer cell motility; this was associated with SPIN90 downregulation. We also found that miR-130b-3p was generated in luminal A-type cancer cells and activated fibroblasts after being secreted via exosomes from cancer cells. Finally, miR-130b-3p increased in SPIN90-downregulated tumor stroma of luminal A breast cancer patients and MCF7 cell-xenograft model mice. Our data demonstrate that miR-130b-3p is a key modulator that downregulates SPIN90 in breast CAFs. The inverse correlation between miR-130b-3p and SPIN90 in tumor stroma suggests that the miR-130b-3p/SPIN90 axis is clinically significant for CAF activation during breast cancer progression.

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“…However, its abundance in healthy tissues renders it an unsuitable tumor-specific marker, and did not comprise the focus of our research. On the other hand, the oncofetal isoform EDA-FN is under investigation as a potential oncomarker, and its role in breast cancer is described elsewhere [49,50].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Extradomain-B Fibronectin is Associated with Invasion of Breast Cancer Cells

Vaidya

Wang

Qian

et al. 2020

Cells

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Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the expression profile of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN) in invasive breast cancer. Analyses of TCGA/GTEx databases and immunostaining of clinical samples found a significant overexpression of EDB-FN in breast tumors, which correlated with poor overall survival. Significant upregulation of EDB-FN was observed in invasive cell populations generated from relatively less invasive MCF7 and MDA-MB-468 cells by long-term TGF-β treatment and acquired chemoresistance. Treatment of the invasive cell populations with an AKT inhibitor (MK2206-HCl) reduced their invasive potential, with a concomitant decrease in their EDB-FN expression, partly through the phosphoAKT-SRp55 pathway. EDB-FN downregulation, with direct RNAi of EDB-FN or indirectly through RNAi of SRp55, also resulted in reduced motility of the invasive cell populations, validating the correlation between EDB-FN expression and invasion of breast cancer cells. These data establish EDB-FN as a promising molecular marker for non-invasive therapeutic surveillance of aggressive breast cancer.

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Extra domain A‐containing fibronectin expression in Spin90‐deficient fibroblasts mediates cancer‐stroma interaction and promotes breast cancer progression

Cited by 13 publications

References 50 publications

Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer

Tumor-derived miR-130b-3p induces cancer-associated fibroblast activation by targeting SPIN90 in luminal A breast cancer

Overexpression of Extradomain-B Fibronectin is Associated with Invasion of Breast Cancer Cells

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