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The matricellular protein WISP2 is an endogenous inhibitor of collagen linearization and cancer metastasis

ABSTRACT: Collagen linearization leads to cancer metastasis and poor prognosis but there are no therapies to target it. In addition to cell-generated mechanical forces, collagen linearization is triggered by the interaction of collagen with WISP1 (CCN4), a TGFb1-induced factor secreted by cancer cells. However, it remains unknown how WISP1 is physiologically regulated and whether it could be targeted to prevent collagen linearization. Here, we show that WISP2 (CCN5), a secreted factor downregulated in tumors, is an endogenous inhibitor of type I collagen (Col I) linearization. Mechanistically, WISP2 prevents WISP1 binding to Col I, thereby inhibiting WISP1-induced Col I linearization. Consequently, restoration of WISP2 via overexpression in tumor cells or via treatments with recombinant WISP2 impairs WISP1-induced or TGFb1-induced cancer cell invasion and spontaneous metastasis in vivo. Overall, this study uncovers WISP2 as an endogenous competitive inhibitor of WISP1 and reveals that collagen linearization is controlled by secreted factors with antagonistic functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE152514 | GEO | 2021/08/27

REPOSITORIES: GEO

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The matricellular protein WISP2 is an endogenous inhibitor of collagen linearization and cancer metastasis

Project description:The matricellular protein WISP2 is an endogenous inhibitor of collagen linearization and cancer metastasis

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Identification of WISP1 as an important survival factor in human mesenchymal stem cells

Project description:WNT-induced secreted protein 1 (WISP1/CCN4), a member of the CCN protein family, acts as a downstream factor of the canonical WNT-signaling pathway. A dysregulated expression of WISP1 often reflects its oncogenic potential by inhibition of apoptosis, a necessary form of cell death that protect cell populations for transformation into malignant phenotypes. WISP1-signaling is also known to affect proliferation and differentiation of human mesenchymal stem cells (hMSCs), which are fundamental for the constitution and maintenance of the musculoskeletal system. Our study emphasizes the importance of WISP1-signaling for cell survival of primary human cells. Therefore, we established a successful down-regulation of endogenous WISP1 transcripts through gene silencing in hMSCs. We were able to demonstrate the consequence of cell death immediately after WISP1 down-regulation took place. Bioinformatical analyses of subsequent performed microarrays from WISP1 down-regulated vs. control samples confirmed this observation. We uncovered several clusters of differential expressed genes important for cellular apoptosis induction and immuno-regulatory processes, thereby indicating TRAIL-induced and p53-mediated apoptosis as well as IFNbeta-signaling. Since all of them act as potent inhibitors for malignant cell growth, in vitro knowledge about the connection with WISP1-signaling could help to find new therapeutic approaches concerning cancerogenesis and tumor growth in musculoskeletal tissues. We established a successful down-regulation of endogenous WISP1 transcripts through gene silencing in hMSCs. Knock-down versus controls.

2014-04-30 | E-GEOD-37603 | biostudies-arrayexpress

Effect of TGFb1 treatment and WISP1 overexpression on 4T1 breast cancer cells

Project description:This study set out to identify TGFb1 transcriptional targets in breast cancer cells. 4T1 breast cancer cells were treated with TGFb1 for 24h and transcripts that were significantly regulated were identified. Wisp1 was identified as one of the genes most highly upregulated by TGFb1. To identify the transcriptional targets of Wisp1, 4T1 cells were then virally transduced to increase Wisp1 expression. The gene expression profiles of Wisp1-overexpressing 4T1 cells were determined and revealed that Wisp1 overexpression does not result in major gene expression changes in 4T1 cells.

2019-07-08 | GSE110912 | GEO

Identification of WISP1 as an important survival factor in human mesenchymal stem cells

2014-04-30 | GSE37603 | GEO

Notch1 - WISP1 Axis Determines Tumor-Regulating Role of Melanoma Stromal Fibroblasts

Project description:Cancer-associated fibroblasts (CAF) are crucial in regulating cancer progression, yet the molecular mechanisms that determine the tumor-regulating function of CAF are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that controls the regulatory role of CAF in melanoma growth, invasion and metastasis, and can be manipulated to reprogram and convert CAF to act as tumor suppressors. The Notch1-determined tumor-regulating function is in part mediated by Wnt-induced secreted protein 1 (WISP1). These findings reveal the Notch1âWISP1 axis as a crucial molecular determinant in governing stromal regulation of tumor progression, and establish this axis as a potential therapeutic target Total RNA obtained from MSCD-SF transduced with Cre-GFP/lentivirus in vitro compared to MSCD-SF transduced with GFP/lentivirus. Samples are duplicates.

2016-05-29 | E-GEOD-65316 | biostudies-arrayexpress

Notch1 - WISP1 Axis Determines Tumor-Regulating Role of Melanoma Stromal Fibroblasts

Project description:Cancer-associated fibroblasts (CAF) are crucial in regulating cancer progression, yet the molecular mechanisms that determine the tumor-regulating function of CAF are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that controls the regulatory role of CAF in melanoma growth, invasion and metastasis, and can be manipulated to reprogram and convert CAF to act as tumor suppressors. The Notch1-determined tumor-regulating function is in part mediated by Wnt-induced secreted protein 1 (WISP1). These findings reveal the Notch1—WISP1 axis as a crucial molecular determinant in governing stromal regulation of tumor progression, and establish this axis as a potential therapeutic target

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WISP2/CCN5 is a prognostic biomarker influenced by tumour purity and fibroblast infiltration in hepatocellular carcinoma

Project description:Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. The dismal outcome is attributable to high frequency of recurrence and metastasis. Therefore, identification of effective biomarkers is a key strategy to inform prognosis and improve survival of HCC patients Methods We analysed expression of WNT-1-induced signalling protein-2 (WISP2) and the prognostic correlation in HCC patients using Oncomine, Kaplan Meier plotter, and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) . We explored the role of WISP2 in HCC using the Cancer Cell Line Encyclopedia (CCLE) and gene microarrays and then assessed the correlation between WISP2 and stromal cells in tumour tissues using the Tumor IMmune Estimation Resource (TIMER). Finally, the role of WISP2 and its relationship with tumour purity and fibroblast infiltration were examined both in vitro and in vivo. Results WISP2 was downregulated in HCC tissues, and high expression of WISP2 was associated with better prognosis in patients with certain clinicopathologic characteristics. Upregulation of WISP2 in HCC was related to inhibition of the malignant phenotype in vitro, but these alterations were not observed in vivo . WISP2 also negatively correlated with tumour purity, and increased infiltration of fibroblasts promoted malignant progression in HCC tissues. The enhanced infiltration ability of fibroblasts was related to upregulated high-mobility group protein 1 (HMGB1) after overexpression of WISP2 in HCC. Conclusions The findings shed light on the anticancer role of WISP2 in HCC, suggest that WISP2 overexpression may serve as a biomarker for better prognosis, and indicate that WISP2 expression is influenced by tumour purity and fibroblast infiltration.

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Wisp inhibits chondrogenic differentiation in heterotopic ossification

Project description:Heterotopic ossification (HO) is the formation of extra-skeletal bone in muscle and soft tissues. Better characterization of the signaling pathways predisposing to HO is critical to identifying therapies directed against this common and potentially debilitating condition. WISP-1 (WNT1-inducible-signaling pathway protein 1) is a CCN family member and is expressed in skeletal cells during bone development or repair. Here, we sought to comprehensively explore the significance of WISP-1 across mouse and human HO. Among CCN family members, local Wisp1 expression was most highly upregulated within experimental trauma-associated HO by RNA sequencing, and increased Wisp1 corresponded to gene markers of osteochondral differentiation. WISP1 immunolocalization demonstrated conserved expression in osteochondral cells across mouse and human HO, including an FOP-like model, post-traumatic model, and human examples of non-genetic HO. Transgenic Wisp1 global knockout demonstrated an increase in cartilage and bone in a trauma-induced HO model. Microarray and in vitro culture of Wisp1 null cells suggested that WISP1 functions as a negative regulator of chondrogenic differentiation, and that Wisp1 deletion results in unrestrained endochondral HO formation. siRNA mediated WISP1 knockdown in human progenitor cells confirmed this finding. Overall, these findings suggest that endogenous WISP1 has pathophysiologic relevance in trauma-induced HO and functions as a negative regulator of ectopic chondrogenesis.

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Effect of TGFb1 treatment and WISP1 overexpression on 4T1 breast cancer cells

Project description:Effect of TGFb1 treatment and WISP1 overexpression on 4T1 breast cancer cells

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Collagen type-V is a danger signal associated with primary graft dysfunction in lung transplantation

Project description:Primary graft dysfunction (PGD) is the leading cause of early mortality after lung transplantation. Anti-collagen type-V (col(V)) immunity has been observed in animal models of ischemia-reperfusion injury (IRI) and in PGD. We hypothesized that collagen type-V is an innate danger signal contributing to PGD pathogenesis. Methods: Anti-col(V) antibody production was detected by flow cytometric assay following cultures of murine CD19+ splenic cells with col(V). Responding murine B cells were phenotyped using surface markers. RNA-Seq analysis was performed on murine CD19+ cells. Levels of anti-col(V) antibodies were measured in 188 recipients from the Lung Transplant Outcomes Group (LTOG) after transplantation. Results: Col(V) induced rapid production of anti-col(V) antibodies from murine CD19+ B cells. Subtype analysis demonstrated innate B-1 B cells bound col(V). Col(V) induced a specific transcriptional signature in CD19+ B cells with similarities to, yet distinct from, B cell receptor (BCR) stimulation. Rapid de novo production of anti-col(V) Abs was associated with an increased incidence of clinical PGD after lung transplant. Conclusions: This study demonstrated that col(V) is an rapidly recognized by B cells and has specific transcriptional signature. In lung transplants recipients the rapid seroconversion to anti-col(V) Ab is linked to increased risk of grade 3 PGD.

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