Epithelial and stromal circadian clocks are inversely regulated by their mechano-matrix environment

Williams, Jack; Yang, Nan; Wood, A.K.; Zindy, Egor; Meng, Qing‐Jun; Streuli, Charles

doi:10.1242/jcs.208223

Cited by 41 publications

(41 citation statements)

References 29 publications

(35 reference statements)

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“…In the U2OS osteosarcoma line, BMAL1 over-expression induces apoptosis, while in CA46 lymphoma cells it increases apoptosis and reduces proliferation, leading to smaller tumours when the cells are injected into mice [ 5 ]. Stromal cells are the origin of osteosarcoma cells, and we have examined clocks in stromal cells [ 52 ]. We found that stromal clocks are regulated oppositely to those in epithelial cells in normal tissues, so it will be interesting to determine possible alterations of clock gene expression in the normal and tumour-associated stromal regions of breast tissue.…”

Section: Discussionmentioning

confidence: 99%

Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours

et al. 2018

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BackgroundCircadian rhythms maintain tissue homeostasis during the 24-h day-night cycle. Cell-autonomous circadian clocks play fundamental roles in cell division, DNA damage responses and metabolism. Circadian disruptions have been proposed as a contributing factor for cancer initiation and progression, although definitive evidence for altered molecular circadian clocks in cancer is still lacking. In this study, we looked at circadian clocks in breast cancer.MethodsWe isolated primary tumours and normal tissues from the same individuals who had developed breast cancer with no metastases. We assessed circadian clocks within primary cells of the patients by lentiviral expression of circadian reporters, and the levels of clock genes in tissues by qPCR. We histologically examined collagen organisation within the normal and tumour tissue areas, and probed the stiffness of the stroma adjacent to normal and tumour epithelium using atomic force microscopy.ResultsEpithelial ducts were disorganised within the tumour areas. Circadian clocks were altered in cultured tumour cells. Tumour regions were surrounded by stroma with an altered collagen organisation and increased stiffness. Levels of Bmal1 messenger RNA (mRNA) were significantly altered in the tumours in comparison to normal epithelia.ConclusionCircadian rhythms are suppressed in breast tumour epithelia in comparison to the normal epithelia in paired patient samples. This correlates with increased tissue stiffness around the tumour region. We suggest possible involvement of altered circadian clocks in the development and progression of breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1053-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours

et al. 2018

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“…Still, adequate customizable models to study these complex interactions are still lacking. In vitro studies using traditional 2D models have provided important insights into relevant pathophysiological processes occurring in breast tissue, and associated mechanisms (Kozlowski et al, 2009;Sung et al, 2013;Jin et al, 2018;Williams et al, 2018). Still, 2D models are reductionist as they fail to recapitulate key architectural features of healthy and diseased tissues, namely by lacking three-dimensionality, forcing artificial cell polarity and failing to mimic native biomechanical properties.…”

Section: Introductionmentioning

confidence: 99%

Reshaping in vitro Models of Breast Tissue: Integration of Stromal and Parenchymal Compartments in 3D Printed Hydrogels

Silva

Coelho

Bidarra

et al. 2020

Front. Bioeng. Biotechnol.

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Breast tissue consists of an epithelial parenchyma embedded in stroma, of heterogeneous and complex composition, undergoing several morphological and functional alterations throughout females' lifespan. Improved knowledge on the crosstalk between parenchymal and stromal mammary cells should provide important insights on breast tissue dynamics, both under healthy and diseased states. Here, we describe an advanced 3D in vitro model of breast tissue, combining multiple components, namely stromal cells and their extracellular matrix (ECM), as well as parenchymal epithelial cells, in a hybrid system. To build the model, porous scaffolds were produced by extrusion 3D printing of peptide-modified alginate hydrogels, and then populated with human mammary fibroblasts. Seeded fibroblasts were able to adhere, spread and produce endogenous ECM, providing adequate coverage of the scaffold surface, without obstructing the pores. On a second stage, a peptide-modified alginate pre-gel laden with mammary gland epithelial cells was used to fill the scaffold's pores, forming a hydrogel in situ by ionic crosslinking. Throughout time, epithelial cells formed prototypical mammary acini-like structures, in close proximity with fibroblasts and their ECM. This generated a heterotypic 3D model that partially recreates both stromal and parenchymal compartments of breast tissue, promoting cell-cell and cell-matrix crosstalk. Furthermore, the hybrid system could be easily dissolved for cell recovery and subsequent analysis by standard cellular/molecular assays. In particular, we show that retrieved cell populations could be discriminated by flow cytometry using cell-type specific markers. This integrative 3D model stands out as a promising in vitro platform for studying breast stroma-parenchyma interactions, both under physiological and pathological settings.

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“…; Williams et al . ). As such, disruption of any single ECM component can, and often does, lead to an enormous array of downstream changes that typically force the establishment of a new dynamic equilibrium and underpin the gross changes in tissue and organ architecture and function typically associated with cancer progression (Mayorca‐Guiliani et al .…”

Section: Defining the Ecm In Health And Diseasementioning

confidence: 97%

Charting the unexplored extracellular matrix in cancer

Filipe

Chitty

Cox

2018

Int J Experimental Path

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The extracellular matrix (ECM) is present in all solid tissues and considered a master regulator of cell behaviour and phenotype. The importance of maintaining the correct biochemical and biophysical properties of the ECM, and the subsequent regulation of cell and tissue homeostasis, is illustrated by the simple fact that the ECM is highly dysregulated in many different types of disease, especially cancer. The loss of tissue ECM homeostasis and integrity is seen as one of the hallmarks of cancer and typically defines transitional events in progression and metastasis. The vast majority of cancer studies place an emphasis on exploring the behaviour and intrinsic signalling pathways of tumour cells. Their goal was to identify ways to target intracellular pathways regulating cancer. Cancer progression and metastasis are powerfully influenced by the ECM and thus present a vast, unexplored repository of anticancer targets that we are only just beginning to tap into. Deconstructing the complexity of the tumour ECM landscape and identifying the interactions between the many cell types, soluble factors and extracellular-matrix proteins have proved challenging. Here, we discuss some of the emerging tools and platforms being used to catalogue and chart the ECM in cancer.

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Epithelial and stromal circadian clocks are inversely regulated by their mechano-matrix environment

Cited by 41 publications

References 29 publications

Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours

Disrupted circadian clocks and altered tissue mechanics in primary human breast tumours

Reshaping in vitro Models of Breast Tissue: Integration of Stromal and Parenchymal Compartments in 3D Printed Hydrogels

Charting the unexplored extracellular matrix in cancer

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