ArticleActa biomaterialia2021
Heterogeneous microenvironmental stiffness regulates pro-metastatic functions of breast cancer cells.
Article in Acta biomaterialia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed.
- High-quantity capture of heterogeneous circulating tumor cellsMaterials today. Bio · 2026Article
- Heterogeneity in cancer: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Biomimetic Scaffold-Based 3D Models for Decoding Cancer Biology and Advancing Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- FAK and Pyk2: Paralogous Kinases with Opposing Roles in Vasculogenic Mimicry in Triple-Negative Breast Cancer.International journal of molecular sciences · 2026Article
- Decoding triple negative breast cancer bone metastasis: from 3D bioprinted models to clinical translation.Journal of nanobiotechnology · 2026Review
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- Nuclear Mechanotransduction Across the Metastatic Cascade: Decoding Spatiotemporal Heterogeneity in Cancer Dissemination.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Multiomic and functional validation of ACSL3, a regulator of fatty acid metabolism, as a lymph node metastasis-associated gene in lung adenocarcinoma.Respiratory research · 2026Article
- Matrix micro/nano-topography drives oncogenic signaling and drug response in a 3D osteosarcoma model.Journal of nanobiotechnology · 2026Article
- Absolute dynamic and relative static: the relationship of glycolysis and OXPHOS in cancer development.Cell death discovery · 2026Review
- Differential AXL expression and Arf1 regulation control stiffness-dependent Golgi organization in breast cancer cells.Journal of cell science · 2026Article
- Modeling and targeting the hostile physicochemical niche in bone metastasis: from experimental platforms to niche-directed therapy.Frontiers in cell and developmental biology · 2026Review
- A mechanobiological hypothesis on bone cement-induced progression of bone metastases.Frontiers in bioengineering and biotechnology · 2026Article
- Collagen dynamics in the breast cancer tumor microenvironment and therapeutic perspectives.Discover oncology · 2025Review
- Effects of Stiffness and Degradability on Cardiac Fibroblast Contractility and Extracellular Matrix Secretion in Three-Dimensional Hydrogel Scaffolds.ACS biomaterials science & engineering · 2025Article
- Stable production of immortalized hPC-MSC-derived extracellular vesicles: integrated cargo analysis and functional validation.Stem cell research & therapy · 2025Article
- A microfluidic rheometer for tumor mechanics and invasion studies.Lab on a chip · 2025Article
- Substrate Stiffness Modulates Fibroblast Extracellular Vesicle Secretion Via Mechanotransduction Pathways.Small (Weinheim an der Bergstrasse, Germany) · 2025Article
- 3D printing-biomimetic local stiff niche enhances glycolysis to boost PDAC cell stem-like phenotype via N6-methyladenosine-suppressed YAP1 mRNA decay.Materials today. Bio · 2025Article
- A microfluidic rheometer for tumor mechanics and invasion studies.bioRxiv : the preprint server for biology · 2025Article
9 more citing papers are in PubMed but not listed here.
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10 authors.
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Abstract
Besides molecular and phenotypic variations observed in cancer cells, intratumoral heterogeneity also occurs in the tumor microenvironment. Correlative stiffness maps of different intratumor locations in breast tumor biopsies show that stiffness increases from core to periphery. However, how different local ECM stiffness regulates key functions of cancer cells in tumor progression remains unclear. Although increased tissue stiffness is an established driver of breast cancer progression, conclusions from 2D cultures do not correspond with newer data from cancer cells in 3D environments. Many past studies of breast cancer in 3D culture fail to recapitulate the stiffness of a real breast tumor or the various local stiffnesses present in a tumor microenvironment. In this study, we developed a series of collagen/alginate hybrid hydrogels with adjustable stiffness to match the core, middle, and peripheral zones of a breast tumor. We used this hydrogel system to investigate effects of different local stiffness on morphology, proliferation, and migration of breast cancer cells. RNA sequencing of cells in hydrogels with different stiffness revealed changes in multiple cellular processes underlying cancer progression, including angiogenesis and metabolism. We discovered that tumor cells in a soft environment enriched YAP1 and AP1 signaling related genes, whereas tumor cells in a stiff environment became more pro-angiogenic by upregulating fibronectin 1 (FN1) and matrix metalloproteinase 9 (MMP9) expression. This systematic study defines how the range of environmental stiffnesses present in a breast tumor regulates cancer cells, providing new insights into tumorigenesis and disease progression at the tumor-stroma interface. STATEMENT OF SIGNIFICANCE: Applied a well-defined hybrid hydrogel system to mimic the tumor microenvironment with heterogeneous local stiffness. Breast cancer cells tended to proliferate in soft core environment while migrate in stiff peripheral environment. Breast cancer cells shift from glycolysis to OXPHOS and fatty acid metabolism responding to stiff matrix microenvironment. The transcriptomic profile of breast cancer cells altered due to microenvironmental stiffness changes.
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