Extracellular matrix stiffness dictates Wnt expression through integrin pathway

Du, Jing; Zhang, Yan; Li, Jing; Du, Shuyuan; Xu, Yuming; Zhang, Lang; Jiang, Li; Wang, Zhao; Chien, Shu; Yang, Chun

doi:10.1038/srep20395

Cited by 167 publications

(150 citation statements)

References 40 publications

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“…The physiological relevance of culturing SFUs versus salispheres can be extrapolated from these following studies: Srinivasan and colleagues used 3D hyaluronate hydrogel and reported that parotid cells retained their progenitor cell markers (KRT5, KRT14, ETV5, and MYC) and expressed low levels of cell differentiation markers (Srinivasan et al, ). ECM stiffness was reported to activate the integrin/focal adhesion kinase pathway, which in turn activated β‐catenin to increase Wnt1 expression in mesenchymal stem cells and chondrocytes (Du et al, ). The Wnt/β‐catenin pathway was implicated in the maintenance of cell polarization in Mist + pancreatic acinar cells (Pin, Rukstalis, Johnson, & Konieczny, ).…”

Section: Discussionmentioning

confidence: 99%

Cell culture of differentiated human salivary epithelial cells in a serum‐free and scalable suspension system: The salivary functional units model

Seo

Lilliu

Elghanam

et al. 2019

J Tissue Eng Regen Med

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Saliva aids in digestion, lubrication, and protection of the oral cavity against dental caries and oropharyngeal infections. Reduced salivary secretion, below an adequate level to sustain normal oral functions, is unfortunately experienced by head and neck cancer patients treated with radiotherapy and by patients with Sjögren's syndrome. No disease‐modifying therapies exist to date to address salivary gland hypofunction (xerostomia, dry mouth) because pharmacotherapies are limited by the need for residual secretory acinar cells, which are lost at the time of diagnosis, whereas novel platforms such as cell therapies are yet immature for clinical applications. Autologous salivary gland primary cells have clinical utility as personalized cell therapies, if they could be cultured to a therapeutically useful mass while maintaining their in vivo phenotype. Here, we devised a serum‐free scalable suspension culture system that grows partially digested human salivary tissue filtrates composing of acinar and ductal cells attached to their native extracellular matrix components while retaining their 3D in vivo spatial organization; we have coined these salivary spheroids as salivary functional units (SFU). The proposed SFU culture system was sub‐optimal, but we have found that the cells could still survive and grow into larger salivary spheroids through cell proliferation and aggregation for 5 to 10 days within the oxygen diffusion rates in vitro. In summary, by using a less disruptive cell isolation procedure as the starting point for primary cell culture of human salivary epithelial cells, we demonstrated that aggregates of cells remained proliferative and continued to express acinar and ductal cell‐specific markers.

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Section: Discussionmentioning

confidence: 99%

Cell culture of differentiated human salivary epithelial cells in a serum‐free and scalable suspension system: The salivary functional units model

Seo

Lilliu

Elghanam

et al. 2019

J Tissue Eng Regen Med

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show abstract

“…Studies have reported that stress stimulates the combined expression of vinculin and paxillin, thereby activating FAK[18, 19, 44] to eventually promote the expression of tumor malignancy markers, such as MMP2, MMP9 and VEGF[45]. During mechanotransduction, the Wnt-independent activation of β-catenin is also initiated by FAK upregulation[46] to increase MMP2 and MMP9 activity, thereby contributing to tumorigenesis[47]. FAK signaling pathway also regulates cancer malignancy by modulating ALDH[48] and CD133[49].…”

Section: Discussionmentioning

confidence: 99%

Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels

Jiang

Zhao

et al. 2019

Biomaterials

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How cancer cells and their anchorage-dependent normal counterparts respond to the adhesion ligand density and stiffness of the same extracellular matrix (ECM) is still not very clear. Here we investigated the effects of ECM adhesion ligand density and stiffness on bone tumor cells (osteosarcoma cells) and bone forming cells (osteoblasts) by using poly (ethylene glycol) diacrylate (PEGDA) and methacrylated gelatin (GelMA) hydrogels. By independently changing the PEGDA and GelMA content in the hydrogels, we achieved crosslinked hydrogel matrix with independently tunable stiffness (1.6, 6 and 25 kPa for 5%, 10%, 15% PEDGA, respectively) and adhesion ligand density (low, medium and high for 0.05%, 0.2%, 0.5% GelMA respectively). By using a series of biochemical and cell biological characterizations as well as in vivo studies, we confirmed that osteosarcoma and osteoblastic cells responded differently to the stiffness and adhesion ligand density within 3D ECM. When cultured within the 3D PEGDA/GelMA hydrogel matrix, osteosarcoma cells are highly dependent on the matrix stiffness via regulating the integrin-mediated focal adhesion (FA) pathway, whereas osteoblasts are highly sensitive to the matrix adhesion ligand density through regulating the integrin-mediated adherens junction (AJ) pathway. However, when seeded on the 2D surface of the hydrogels, osteosarcoma cells behaved differently and became sensitive to the matrix adhesion ligand density because they were “forced” to attach to the substrate, similar to anchorage-dependent osteoblasts. This study might provide new insights into rational design of scaffolds for generating in vitro tumor models to test anticancer therapeutics and for regenerating tissue to repair defects.

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“…Previous studies have shown that Wnt signaling and integrin β3 act in a coordinated manner to increase tumorigenesis [46]. Specifically, it has been shown in a mouse model of mammary tumorigenesis that integrin β3 is expressed prominently in transgenic mice with wnt-1 signaling pathway overexpression [30].…”

Section: Discussionmentioning

confidence: 99%

HOXD3 Plays a Critical Role in Breast Cancer Stemness and Drug Resistance

Zhang

Cao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Homeobox D3 (HOXD3) is a member of the homeobox family of genes that is known primarily for its transcriptional regulation of morphogenesis in all multicellular organisms. In this study, we sought to explore the role that HOXD3 plays in the stem-like capacity, or stemness, and drug resistance of breast cancer cells. Methods: Expression of HOXD3 in clinical breast samples were examined by RT-PCR and immunohistochemistry. HOXD3 expression in breast cancer cell lines were analyzed by RT-PCR and western blot. Ability of drug resistance in breast cancer cells were elevated by MTT cell viability and colony formation assays. We examined stemness using cell fluorescent staining, RT-PCR and western blot for stem cell marker expression. Finally, activity of wnt signaling was analyzed by FOPflash luciferase assays. RT-PCR and western blot were performed for downstream genes of wnt signaling. Results: We demonstrated that HOXD3 is overexpressed in breast cancer tissue as compared to normal breast tissue. HOXD3 overexpression enhances breast cancer cell drug resistance. Furthermore, HOXD3 upregulation in the same cell lines increased sphere formation as well as the expression levels of stem cell biomarkers, suggesting that HOXD3 does indeed increase breast cancer cell stemness. Because we had previously shown that HOXD3 expression is closely associated with integrin β3 expression in breast cancer patients, we hypothesized that HOXD3 may regulate breast cancer cell stemness and drug resistance through integrin β 3. Cell viability assays showed that integrin β 3 knockdown increased cell viability and that HOXD3 could not restore cancer cell stemness or drug resistance. Given integrin β 3’s relationship with Wnt/β-catenin signaling, we determine whether HOXD3 regulates integrin β 3 activity through Wnt/β-catenin signaling. We found that, even though HOXD3 increased the expression of Wnt/β-catenin downstream genes, it did not restore Wnt/β-catenin signaling activity, which was inhibited in integrin β3 knockdown breast cancer cells. Conclusion: We demonstrate that HOXD3 plays a critical role in breast cancer stemness and drug resistance via integrin β3-mediated Wnt/β-catenin signaling. Our findings open the possibility for improving the current standard of care for breast cancer patients by designing targeted molecular therapies that overcome the barriers of cancer cell stemness and drug resistance.

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Extracellular matrix stiffness dictates Wnt expression through integrin pathway

Cited by 167 publications

References 40 publications

Cell culture of differentiated human salivary epithelial cells in a serum‐free and scalable suspension system: The salivary functional units model

Cell culture of differentiated human salivary epithelial cells in a serum‐free and scalable suspension system: The salivary functional units model

Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels

HOXD3 Plays a Critical Role in Breast Cancer Stemness and Drug Resistance

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