A Biomimetic Hyaluronic Acid Hydrogel Models Mass Dormancy in Brain Metastatic Breast Cancer Spheroids

Kondapaneni, Raghu Vamsi; Shevde, Lalita A.; Rao, Shreya

doi:10.1002/adbi.202200114

Cited by 11 publications

(10 citation statements)

References 59 publications

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“…The assembly of spheroid-like structures on HA-based composite materials has been previously reported [ 60 ]. These structures reproduce the 3D architecture of tumors, which is why their use as models for screening therapeutic drugs against cancer has been highlighted [ 60 , 61 ]. The cell proliferation and its successful growth on nanofibers depend on the establishment of the interaction of HA with the cellular surface marker CD44 receptor.…”

Section: Resultsmentioning

confidence: 99%

Novel PVA–Hyaluronan–Siloxane Hybrid Nanofiber Mats for Bone Tissue Engineering

Sánchez-Téllez,

Baltierra-Uribe,

Vidales-Hurtado

et al. 2024

Polymers

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Hyaluronan (HA) is a natural biodegradable biopolymer; its biological functions include cell adhesion, cell proliferation, and differentiation as well as decreasing inflammation, angiogenesis, and regeneration of damaged tissue. This makes it a suitable candidate for fabricating nanomaterials with potential use in tissue engineering. However, HA nanofiber production is restricted due to the high viscosity, low evaporation rate, and high surface tension of HA solutions. Here, hybrids in the form of continuous and randomly aligned polyvinyl alcohol (PVA)–(HA)–siloxane nanofibers were obtained using an electrospinning process. PVA–HA fibers were crosslinked by a 3D siloxane organic–inorganic matrix via sol-gel that restricts natural hydrophilicity and stiffens the structure. The hybrid nanofiber mats were characterized by FT-IR, micro-Raman spectroscopy, SEM, and biological properties. The PVA/HA ratio influenced the morphology of the hybrid nanofibers. Nanofibers with high PVA content (10PVA-8 and 10PVA-10) form mats with few beaded nanofibers, while those with high HA content (5PVA-8 and 5PVA-10) exhibit mats with mound patterns formed by “ribbon-like” nanofibers. The hybrid nanofibers were used as mats to support osteoblast growth, and they showed outstanding biological properties supporting cell adhesion, cell proliferation, and cell differentiation. Importantly, the 5PVA-8 mats show 3D spherical osteoblast morphology; this suggests the formation of tissue growth. These novel HA-based nanomaterials represent a relevant advance in designing nanofibers with unique properties for potential tissue regeneration.

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Section: Resultsmentioning

confidence: 99%

Novel PVA–Hyaluronan–Siloxane Hybrid Nanofiber Mats for Bone Tissue Engineering

Sánchez-Téllez,

Baltierra-Uribe,

Vidales-Hurtado

et al. 2024

Polymers

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“…Varying the RGD concentration provided varying levels of adhesivity and allowed us to examine how such environments may impact tumor cell dormancy. Generally, studies investigating the role of biophysical or biochemical cues in regulating dormancy in the context of BCBM have been limited 22,25,27–29 . To this end, our group previously examined the impact of biophysical cues and how it regulates dormancy in brain metastatic breast cancer cells in a biomimetic HA hydrogel 22 .…”

Section: Discussionmentioning

confidence: 99%

“…We performed immunofluorescence staining for p‐ERK and p‐p38, as these markers have been shown to be differentially expressed between proliferative and dormant cells in previous studies 27,28 . To determine the percentage of p‐ERK and p‐p38 positive cells on day 5, cells were gently trypsinized for ~5 min, allowing their detachment from the HA hydrogels.…”

Section: Methodsmentioning

confidence: 99%

“…We performed immunofluorescence staining for p-ERK and p-p38, as these markers have been shown to be differentially expressed between proliferative and dormant cells in previous studies. 27,28 To determine the percentage of p-ERK and p-p38 positive cells on day 5, cells were gently trypsinized for $5 min, allowing their detachment from the HA hydrogels. Subsequently, these cells were transferred to a 96-well plate, where they underwent fixation, permeabilization, and blocking, following the previously outlined procedures.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

“…Generally, studies investigating the role of biophysical or biochemical cues in regulating dormancy in the context of BCBM have been limited. 22,25,[27][28][29] To this end, our group previously examined the impact of biophysical cues and how it regulates dormancy in brain metastatic breast cancer cells in a biomimetic HA hydrogel. 22 However, the impact of biochemical cues (e.g., varying levels of cell adhesivity) was not tested.…”

Section: Involvement Of β1 Integrin In Mediating Cell Phenotypementioning

confidence: 99%

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Varying the RGD concentration on a hyaluronic acid hydrogel influences dormancy versus proliferation in brain metastatic breast cancer cells

Goodarzi,

Lane,

Rao

2023

J Biomedical Materials Res

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A majority of breast cancer deaths occur due to metastasis of cancer cells to distant organs. In particular, brain metastasis is very aggressive with an extremely low survival rate. Breast cancer cells that metastasize to the brain can enter a state of dormancy, which allows them to evade death. The brain microenvironment provides biophysical, biochemical, and cellular cues, and plays an important role in determining the fate of dormant cancer cells. However, how these cues influence dormancy remains poorly understood. Herein, we employed hyaluronic acid (HA) hydrogels with a stiffness of ~0.4 kPa as an in vitro biomimetic platform to investigate the impact of biochemical cues, specifically alterations in RGD concentration, on dormancy versus proliferation in MDA‐MB‐231Br brain metastatic breast cancer cells. We applied varying concentrations of RGD peptide (0, 1, 2, or 4 mg/mL) to HA hydrogel surfaces and confirmed varying degrees of surface functionalization using a fluorescently labeled RGD peptide. Post functionalization, ~10,000 MDA‐MB‐231Br cells were seeded on top of the hydrogels and cultured for 5 days. We found that an increase in RGD concentration led to changes in cell morphology, with cells transitioning from a rounded to spindle‐like morphology as well as an increase in cell spreading area. Also, an increase in RGD concentration resulted in an increase in cell proliferation. Cellular dormancy was assessed using the ratio of phosphorylated extracellular signal‐regulated kinase 1/2 (p‐ERK) to phosphorylated p38 (p‐p38) positivity, which was significantly lower in hydrogels without RGD and in hydrogels with lowest RGD concentration compared to hydrogels functionalized with higher RGD concentration. We also demonstrated that the HA hydrogel‐induced cellular dormancy was reversible. Finally, we demonstrated the involvement of β1 integrin in mediating cell phenotype in our hydrogel platform. Overall, our results provide insight into the role of biochemical cues in regulating dormancy versus proliferation in brain metastatic breast cancer cells.

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Breast Cancer Cells Exhibit Mesenchymal–Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness

Sankhe,

Sacco,

Lawton

et al. 2024

Advanced Biology

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Mesenchymal–epithelial transition (MET) is essential for tissue and organ development and is thought to contribute to cancer by enabling the establishment of metastatic lesions. Despite its importance in both health and disease, there is a lack of in vitro platforms to study MET and little is known about the regulation of MET by mechanical cues. Here, hyaluronic acid‐based hydrogels with dynamic and tunable stiffnesses mimicking that of normal and tumorigenic mammary tissue are synthesized. The platform is then utilized to examine the response of mammary epithelial cells and breast cancer cells to dynamic modulation of matrix stiffness. Gradual softening of the hydrogels reduces proliferation and increases apoptosis of breast cancer cells. Moreover, breast cancer cells exhibit temporal changes in cell morphology, cytoskeletal organization, and gene expression that are consistent with mesenchymal–epithelial plasticity as the stiffness of the matrix is reduced. A reduction in matrix stiffness attenuates the expression of integrin‐linked kinase, and inhibition of integrin‐linked kinase impacts proliferation, apoptosis, and gene expression in cells cultured on stiff and dynamic hydrogels. Overall, these findings reveal intermediate epithelial/mesenchymal states as cells move along a matrix stiffness‐mediated MET trajectory and suggest an important role for matrix mechanics in regulating mesenchymal–epithelial plasticity.

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A Biomimetic Hyaluronic Acid Hydrogel Models Mass Dormancy in Brain Metastatic Breast Cancer Spheroids

Cited by 11 publications

References 59 publications

Novel PVA–Hyaluronan–Siloxane Hybrid Nanofiber Mats for Bone Tissue Engineering

Novel PVA–Hyaluronan–Siloxane Hybrid Nanofiber Mats for Bone Tissue Engineering

Varying the RGD concentration on a hyaluronic acid hydrogel influences dormancy versus proliferation in brain metastatic breast cancer cells

Breast Cancer Cells Exhibit Mesenchymal–Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness

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