Stiffness Increases with Myofibroblast Content and Collagen Density in Mesenchymal High Grade Serous Ovarian Cancer
Open accessAbstract
Women diagnosed with high-grade serous ovarian cancers (HGSOC) are still likely to exhibit a bad prognosis, particularly when suffering from HGSOC of the Mesenchymal molecular subtype (50% cases). These tumors show a desmoplastic reaction with accumulation of extracellular matrix proteins and high content of cancer-associated fibroblasts. Using patient-derived xenograft mouse models of Mesenchymal and Non-Mesenchymal HGSOC, we show here that HGSOC exhibit distinct stiffness depending on their molecular subtype. Indeed, tumor stiffness strongly correlates with tumor growth in Mesenchymal HGSOC, while Non-Mesenchymal tumors remain soft. Moreover, we observe that tumor stiffening is associated with high stromal content, collagen network remodeling, and MAPK/MEK pathway activation. Furthermore, tumor stiffness accompanies a glycolytic metabolic switch in the epithelial compartment, as expected based on Warburg's effect, but also in stromal cells. This effect is restricted to the central part of stiff Mesenchymal tumors. Indeed, stiff Mesenchymal tumors remain softer at the periphery than at the core, with stromal cells secreting high levels of collagens and showing an OXPHOS metabolism. Thus, our study suggests that tumor stiffness could be at the crossroad of three major processes, i.e. matrix remodeling, MEK activation and stromal metabolic switch that might explain at least in part Mesenchymal HGSOC aggressiveness.
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The hanging drop technique acts as a "low-stiffness" model as compared to traditional polystyrene plastic culture dishes.
“The simplicity of the model has enabled it to act as a “low-stiffness” model as compared to traditional polystyrene plastic culture dishes (Mieulet et al., 2021).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Mieulet et al., 2021
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Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Yee, C., Dickson, K.-A., Muntasir, M. N., Ma, Y., & Marsh, D. J. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.836984 · Cited by 66 · see citing works
- Authors
- Mieulet, V., Garnier, C., Kieffer, Y., Guilbert, T., Nemati, F., Marangoni, E., Renault, G., Chamming’s, F., Vincent-Salomon, A., & Mechta-Grigoriou, F.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Institut Curie (FR)
- Université Paris Cité (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Corresponding author
- Mieulet, Virginie
- ORCID
- Venue
- Scientific Reports
- Published
- 2021-02-18
- Volume
- 11
- Issue
- 1
- Pages
- 4219-4219
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7892556
- OpenAlex
- W3129745115
- Cited by
- 79
- References
- 121
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 12 · 2023: 18 · 2022: 18 · 2021: 4
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Institut National de la Santé et de la Recherche Médicale (Permanent position)
- Ministère de l'Enseignement Supérieur et de la Recherche (MERT)
- Fondation pour la Recherche Médicale (Bioinformatician)
- Institut Cochin Paris
- Institut Curie (Permanent position)
- Assistance Publique - Hôpitaux de Paris
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor stiffness, high-grade serous ovarian cancer, cancer-associated fibroblasts, collagen density, extracellular matrix remodeling, tumor microenvironment, Warburg effect, glycolytic metabolism, oxidative phosphorylation, patient-derived xenografts, tumor growth, tumor heterogeneity
- MeSH terms
- Animals, Collagen, Female, Humans, Mesoderm, Ovarian Neoplasms, Gene Expression Regulation, Neoplastic, Stromal Cells, Cystadenocarcinoma, Serous, MAP Kinase Signaling System, Cell Line, Tumor, Mice, Myofibroblasts
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