Biology subjects

Merry, C.

Publications and source records attributed to Merry, C..

2 recordsLinked to original sources

bioRxiv2025

β1 Integrin-FAK-Piezo1 signalling axis drives in-situ stiffening mediated ECM remodelling and invasion of 3D breast epithelium

Stiffening of tissue is a hallmark of cancer progression, driving invasive phenotypes through complex interactions between cells and their extracellular matrix (ECM). However, the mechanisms linking mechanical cues to ECM remodelling and invasion remain incompletely understood. Here, using an in-situ stiffening model that allows for modulation of ECM stiffness around fully formed normal mammary acini embedded in their native ECM microenvironment, we identify critical steps in basement membrane (BM) and stromal ECM remodelling during invasion and discover the molecular mechanisms driving this process. We find that stiffening of the ECM around normal mammary acini results in rapid loss and degradation of laminin (LN) and upregulation of the fibronectin (FN) secretion around the acini. This priming phase is followed by the onset of invasion which requires localized upregulation of LN production and ECM remodelling. Mechanistically, ECM production and remodelling as well as invasion is mediated by {beta}1 integrin-FAK signalling, which activates mechanosensitive ion channels (MSCs). Further, we identify Piezo1 as the MSC downstream of {beta}1 integrin-FAK that drives BM disruption and stromal ECM remodelling. Taken together, our results identify the mechanisms by which stiffness can trigger invasive phenotypes from normal tissues.

cell biology↗

bioRxiv2019

Primary human macrophages are polarized towards pro-inflammatory phenotypes in alginate hydrogels

Dysregulated macrophage function is implicated in a wide range of disorders. In vitro hydrogel culture systems are often used as matrices to model and explore the effect of various external stimuli on macrophage polarization and behaviour. Here, we show that 3D alginate hydrogels are not "macrophage inert" and instead help to direct the maturation of primary human macrophages towards specific phenotypes. We compared polarization of M1-like and M2-like cells activated on planar substrates or in 3D alginate hydrogels (with or without adhesion motifs (RGD)). We show that culture in 3D alginate systems selectively alters M2 polarisation following activation; cells show a 2.6-fold increase in CD86 expression compared to cells matured on planar controls, and increase IL1{beta} cytokine secretion even in response to an M2-like stimulus (LPS alone in the absence of IFN{gamma}). Our results suggest that alginate materials may intrinsically stimulate M2 macrophages to acquire a unique polarization state (resembling M2b), characterized by enhanced expression of CD86 and IL1{beta} secretion while retaining low IL12 and high IL10 secretion typical for M2 macrophages. This has important implications for researchers using alginate hydrogels to study macrophage behavior in culture and co-culture systems, as alginate itself may induce direct phenotypic changes independently or in conjunction with other stimuli.

immunology↗