The matricellular protein WISP2 is an endogenous inhibitor of collagen linearization and cancer metastasis
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ABSTRACT:
PROVIDER: PRJNA639564 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12017951_1.fastq.gz | Fastqsanger.gz | |||
| SRR12017951_2.fastq.gz | Fastqsanger.gz | |||
| SRR12017952_1.fastq.gz | Fastqsanger.gz | |||
| SRR12017952_2.fastq.gz | Fastqsanger.gz | |||
| SRR12017953_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-08-27 | GSE152514 | GEO
Project description:Collagen remodeling contributes to many physiologic and pathologic processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison with normal tissues. Consequently, genetic or pharmacologic restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:WISP1 ratio. SIGNIFICANCE: Two secreted factors, WISP1 and WISP2, antagonistically regulate collagen linearization, and therapeutically increasing the WISP2:WISP1 ratio in tumors limits collagen linearization and inhibits metastasis.See related commentary by Barcus and Longmore, p. 5611.
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Project description:We determined whether collagen is upregulated in colorectal liver metastasis tissue (CRLM). We previously showed that naturally occurring peptides of collagen type I were elevated in the urine of patients with colorectal liver metastasis (CRLM). CRLM tissue was compared to healthy adjacent liver tissue (controls) using high resolution mass spectrometry. Twenty-two different collagen alpha chains were identified, 19 of which were significantly upregulated (P<0.05) in CRLM tissue compared with control tissue. We observed expression of four collagen alpha chains which were absent or low expressed in healthy colon and control tissue, but were highly present in CRC and CRLM tissues analyzed. This expression pattern was also observed for six non-collagen colon specific proteins. Two of these proteins (CDH17 and PPP1R1B/DARP-32) were not known to be differently expressed in CRLM in comparison to healthy liver tissue. Furthermore, 16 of 20 identified proteins related to collagen synthesis were upregulated, indicating increased synthesis of collagen in CRLM. Cross-validation of the mass spectrometry data with immunohistochemistry for collagen type XII confirmed the significant upregulation of collagen type XII in CRLM. This study shows that the majority of collagen types are upregulated in CRLM compared to control tissue most likely as a result of an increased collagen turnover and changes in the collagen supramolecular structure. This research provides further understanding of morphologic changes in extracellular matrix of CRLM and the finding of proteins and peptides that might be specific for tumor metastasis in liquid biopsies.
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Project description:In this study, we sought to identify differentially expressed collagen/integrin genes in PNENs in order to understand the molecular mechanisms underlying the development of stroma-associated fibrosis for invasion and metastasis. We compared collagen/integrin gene expression profiling between PNE tumors (PNETs) and PNE carcinomas (PNECs) using a two-stage design. First, we used PCR Array System for 84 ECM-related genes, and among them, we found COL1A2, COL3A1, COL5A2, ITGA5, ITGAV, and ITGB1 functionally involved in the formation of the stroma-associated fibrosis among PNENs histological subtypes. Second, we examined the clinical association between the six collagen/integrin genes in tumor tissues from 24 patients with surgically excised PNENs.However, the pathological exam of their resected tissues demonstrated that 10 developed lymph node metastasis and 7 distant metastasis. We demonstrated and validated up regulation of the six fibrogenic genes in PNECs and down regulation in PNETs that were significantly associated with metastasis-free and overall survival (P<0.05). Our study implicates up regulation of fibrogenic genes as a critical molecular event leading to lymph node and distant metastasis in PNENs.
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Project description:Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to M2 phenotype via the α2β1 integrin/NF-κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8+ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8+ T cells and abolishes brain metastasis. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrMs-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression, and blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.
2024-03-22 | GSE261941 | GEO
Project description:Collagen, a major component of the extracellular matrix, is significantly upregulated in colorectal liver metastasis (CRLM) compared to liver tissue. Expression levels of specific collagen types in CRLM resemble those in colorectal cancer (CRC) and colon tissue. We investigated whether the collagen hydroxylation pattern from the primary tumor also migrates with the metastatic tumor. The degree of collagen alpha-1(I) hydroxylation in colon, CRC, liver, and CRLM tissue in the same individuals (n=14) was studied with mass spectrometry. The degree of hydroxylation was investigated in 36 collagen alpha-1(I) peptides, which covered 54% of the triple helical region. The average degree of hydroxylation in liver tissue was similar to that in colon tissue. The overall degree of hydroxylation was significantly lower (9% +/- 14%) in CRC tissue and also significantly lower (12% +/-22%) in CRLM tissue compared to colon or liver tissue. Still, in previous research of liver and CRLM enzymes involved in collagen hydroxylation were found to be upregulated, whereas P4HB (4-prolyl hydroxylase beta unit) was downregulated. Furthermore, 11 peptides are present with a specific number of hydroxylations that are significantly different between CRLM and liver tissue; these peptides could be candidates for the detection of CRLM. For one of these eleven peptides, a matching naturally occurring peptide in urine has been identified as being significantly different between patients suffering from CRLM and healthy controls. We conclude that the degree of hydroxylation in CRC and CRLM tumor tissue is in general significantly downregulated in comparison to healthy colon and liver tissue. The hydroxylation pattern in CRLM resemble partly the pattern in liver, primary colorectal cancer and colon.
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