Collagen fiber density observed in metastatic ovarian cancer promotes tumor cell adhesion
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Collagen type I, a key structural component of the extracellular matrix (ECM), is frequently altered in cancer, with altered fiber organization at the primary tumor site linked to metastasis and poor patient outcomes. Here, we demonstrate that collagen fibers are also altered in metastatic sites such as the omentum of patients with high-grade serous ovarian cancer (HGSOC). Specifically, we observed a significant increase in fiber density, alignment, and width. To determine if the increase in fiber density supports metastasis, we used a semi-interpenetrating methacrylated gelatin (gelMA) network in combination with increasing fibrillar collagen. Cancer cells had significantly increased adhesion as collagen fiber density increased. To determine the responsible mechanisms, we used orthogonal systems to examine 1) the different adhesion peptides exposed in collagen (GFOGER) and gelatin (RGD), and 2) the physical structure of fibers. Cells had minimal response to GFOGER, either alone or in combination with RGD, suggesting that increased adhesion did not result from this collagen-specific interaction. Cell adhesion was significantly higher on electrospun PCL-gelatin fibers compared to flat PCL-gelatin substrates, suggesting that increased cell adhesion resulted from fiber structure. We next investigated the cellular mechanisms involved in increased adhesion on gelMA/coll and found that actin polymerization, but not myosin II contractility, was needed. We further demonstrated that cells on fibrous gels had more robust actin polymerization, and that this resulted in greater adhesion strength. Combined, these results suggest that the increase in collagen fibers with tumor metastasis will support the development of additional metastases. STATEMENT OF SIGNIFICANCE: This work advances the evaluation of the matrisome of the omentum, the most common metastatic site in advanced ovarian cancer by characterizing how collagen fibers change with disease progression. To examine the effect of collagen fibers on metastasis, we utilized a suite of in vitro biomaterials to identify a novel role for collagen fibers in supporting cell adhesion through increased actin dynamics during nascent adhesion formation, which results in increased adhesion strength at later times.
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Acta BiomaterialiaTL;DR
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UW Comprehensive Cancer Center SupportA Point-Scanning Confocal Microscope for the Biomedical SciencesElevated collagen I and fibronectin in the ovarian cancer pre-metastatic nicheThe role of multi-cellular aggregates vs. individual tumor cells in metastasis of high-grade serous ovarian cancerAutomated Tissue MicroarrayerEngineered ECM platforms to analyze progression in high grade serous ovarian cancerAutomated Tissue MicroarrayerNational Science Foundation Division of Materials Research Grant DMR-2309000Elevated collagen I and fibronectin in the ovarian cancer pre-metastatic nicheEngineered ECM platforms to analyze progression in high grade serous ovarian cancerThe role of multi-cellular aggregates vs. individual tumor cells in metastasis of high-grade serous ovarian cancerAssociation for Laboratory Medicine FundingAutomated Tissue MicroarrayerNational Institutes of Health Office of the Director Grant S10 OD034394-0Protocol Review and Monitoring SystemUniversity of Wisconsin-Madison FundingMaterials Research Science and Engineering Center, Harvard University FundingNational Science Foundation Funding