Interstitial flow potentiates TGF-β/Smad-signaling activity in lung cancer spheroids in a 3D-microfluidic chip

Rahman, Zaid; Bordoloi, Ankur Deep; Rouhana, Haifa; Tavasso, Margherita; van der Zon, Gerard; Garbin, Valeria; ten Dijke, Peter; Boukany, Pouyan E.

doi:10.1039/d3lc00886j

Cited by 4 publications

(2 citation statements)

References 60 publications

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“…We then exposed the µ-Slide to 45 s of UV-light (365 nm) using a lamp, followed by addition of 200 µL culture medium. Recombinant TGF-β (stock concentration 5 µg/mL was diluted in culture medium to a final concentration of 10 ng/mL 74,75 . Batimastat (BB-94) broad spectrum MMP-inhibitor (stock concentration 1 mM) from Abcam was diluted to 30 µ in culture medium 76 .…”

Section: D Invasion Assaysmentioning

confidence: 99%

“…The permeability, K of a hydrogel can be obtained from Darcy's Law by estimating the flow velocity of tracer particles through the material. To do this, we used a microfluidic platform equipped with three channels, where the middle channel was filled with GelMA hydrogel and crosslinked by a UV-light source (365 nm) 75 . The top and bottom channels were operated using a pressure pump device to create a pressure gradient that drives the flow through the hydrogel channel at room temperature.…”

Section: Gelma Hydrogel Permeability Analysismentioning

confidence: 99%

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EMT-dependent cell-matrix interactions are linked to unjamming transitions in cancer spheroid invasion

van der Net,

Rahman,

Bordoloi

et al. 2024

Preprint

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The plasticity of cancer cells allows them to switch between different migration modes, promoting their invasion into the extracellular matrix (ECM) and hence increasing the risks of metastasis. Epithelial-to-mesenchymal transitions (EMT) and unjamming transitions provide two distinct pathways for cancer cells to become invasive, but it is still unclear to what extent these pathways are connected. Here we addressed this question by performing 3D spheroid invasion assays of lung adenocarcinoma (A549, epithelial) and melanoma (MV3, mesenchymal-like) cancer cell lines in collagen-based hydrogels, where we varied both the invasive character of the cells (using Transforming Growth Factor (TGF)-$\beta$ to promote EMT and matrix metalloprotease (MMP) inhibition to block cell-mediated matrix degradation) and the porosity of the matrix. Using a quantitative image analysis method to track spheroid invasion, we discovered that the onset time of invasion mostly depended on the matrix porosity and corresponded with vimentin levels, while the subsequent spheroid expansion rate mostly depended on metalloprotease MMP1 levels and thus cell-matrix interaction. Morphological analysis revealed that spheroids displayed solid-like (non-invasive) behavior in small-pore hydrogels and switched to fluid-like (strand-based) or gas-like (disseminating cells) phases in large-pore hydrogels and when cells were more mesenchymal-like. Our findings are consistent with unjamming transitions as a function of cell motility and matrix confinement predicted in recent models for cancer invasion, but show that cell motility and matrix confinement are coupled via EMT-dependent matrix degradation.

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Section: D Invasion Assaysmentioning

confidence: 99%

Section: Gelma Hydrogel Permeability Analysismentioning

confidence: 99%