Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs

Feinberg, Tamar; Zheng, Huiyong; Li, Rui; Wicha, Max S.; Yu, Michael; Weiss, Stephen J.

doi:10.1016/j.devcel.2018.08.025

Cited by 57 publications

(56 citation statements)

References 52 publications

(108 reference statements)

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“…These tumors, which grow confined inside the mammary ducts, have been recently shown to display large strands of collectively moving cells associated with the transition from in situ to the invasive stage of the tumor development ( 16 ). Additionally, the breast neoplastic invasive switch requires the activity of matrix proteases for breaching out of the duct ( 17,18 ).…”

Section: Introductionmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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While mutations leading to a fragile envelope of the cell nucleus are well known to cause diseases such as muscular dystrophies or accelerated aging, the pathophysiological consequences of the recently discovered mechanically induced nuclear envelope ruptures in cells harboring no mutation are less known. Here we show that repeated loss of nuclear envelope integrity in nuclei experiencing mechanical constraints promotes senescence in nontransformed cells, and induces an invasive phenotype including increased collagen degradation in human breast cancer cells, both in vitro and in a mouse xenograft model of breast cancer progression. We show that these phenotypic changes are due to the presence of chronic DNA damage and activation of the ATM kinase. In addition, we found that depletion of the cytoplasmic exonuclease TREX1 is sufficient to abolish the DNA damage in mechanically challenged nuclei and to suppress the phenotypes associated with the loss of nuclear envelope integrity. Our results also show that TREX1-dependent DNA damage induced by physical confinement of tumor cells inside the mammary duct drives the progression of in situ breast carcinoma to the invasive stage. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. Main text:( 16,21-23 ), and corresponds to cells squeezing each other as they move. These deformed nuclei were also more often positive for γH2AX than less deformed ones, and in general displayed more intense γH2AX staining than nuclei in the bulk of the tumor ( Fig. 1A-C). This suggests that, at the in situ stage of human breast carcinoma, strands of motile cells at the periphery of the tumor exhibit pronounced nuclear deformation, associated with elevated DNA damage.We then investigated a xenograft mouse model based on the intraductal (intra-nipple) injection of transformed human breast MCF10DCIS.com (DCIS) cells, which are derived from the nontransformed MCF10A cell line, and that recapitulates the transition from in situ to invasive stages of breast cancer progression ( 17,24 ). Tumors at various stages were analyzed. In situ tumors (further divided in early and advanced stages based on the continuity of the myoepithelial layer) are characterized by a myoepithelial layer (stained with smooth muscle actin) surrounding human xenograft cells that were identified by the human-specific KU70 antibody. In order to verify whether human tumor cells similarly experience DNA damage in the tumor xenografts, tumor sections were stained with γH2AX ( Fig. 1E-F, Fig. S1A). Similar to human tumor specimens, xenograft tumors displayed numerous deformed nuclei, mostly found at the periphery of the tumor mass, close to the myoepithelium, especially in ducts inflated with large tumors (Fig. 1E-F), and enriched in regions showing micro-invasive foci. Strikingly, these regions were also enriched in γH2AX-positive nuclei (Fig. 1F). Since γH2AX is also known...

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Section: Introductionmentioning

confidence: 99%

Compromised nuclear envelope integrity drives tumor cell invasion

Nader

Agüera-González

Routet

et al. 2020

Preprint

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“…For example, patterning of collagen fibers in the mammary gland stroma regulates the orientation of TEBs during branching morphogenesis (Brownfield et al, 2013). Recent publications reported important role of fibroblasts in regulation of ECM composition, abundance and organization, and thereby in regulation of mammary epithelial branching morphogenesis (Feinberg et al, 2018;Hammer et al, 2017;Koledova et al, 2016;Morsing et al, 2016;Peuhu et al, 2017). We found that FGF signaling in fibroblasts regulates expression of several ECM genes, including collagens.…”

Section: Discussionmentioning

confidence: 63%

A pleiotropic role for FGF signaling in mammary gland stromal fibroblasts

Koledová

Sumbal

2019

Preprint

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Running title: Role for FGF2 in mammary fibroblasts Summary statementFGF signaling in mammary fibroblasts regulates fibroblast proliferation, migration, extracellular matrix production and remodeling, and fibroblast-mediated mammary epithelial branching morphogenesis. AbstractFibroblast growth factor (FGF) signaling is crucial for mammary gland development. While multiple roles for FGF signaling in the epithelium were described, the function of FGF signaling in mammary stroma has not been elucidated. In this study, we investigated FGF signaling in mammary fibroblasts. We found that mammary fibroblasts express FGF receptors 1 and 2 and respond to FGF ligands. In particular, FGF2 and FGF9 induce sustained ERK1/2 signaling and promote fibroblast proliferation and migration in 2D. Intriguingly, only FGF2 induces fibroblast migration in 3D extracellular matrix (ECM) through regulation of actomyosin cytoskeleton and promotes force-mediated collagen remodeling by mammary fibroblasts. Moreover, FGF2 regulates production of ECM proteins by mammary fibroblasts, including collagens, fibronectin, osteopontin, and matrix metalloproteinases. Finally, we show that FGF2 signaling in mammary fibroblasts enhances fibroblast-induced branching of mammary epithelium. Our results demonstrate a pleiotropic role for FGF signaling in mammary fibroblasts with implications for regulation of mammary stromal functions and epithelial branching morphogenesis.

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“…We show that ID4 suppresses collagen synthesis and deposition around TEBs, which may otherwise act as a physical barrier to impede invasion. In support of this idea, ectopic deposition of collagen by mammary epithelial cells induced by exogeneous TGF-β, or forced expression of recombinant type I collagen which is resistant to collagenase attack, causes ensheathment of TEBs by collagen, and retardation of ductal elongation (Feinberg, Zheng et al, 2018, Silberstein et al, 1990).…”

Section: Discussionmentioning

confidence: 96%

Inhibitor of Differentiation 4 (ID4) represses myoepithelial differentiation of mammary stem cells through its interaction with HEB

Holliday¹,

Roden²,

Junankar³

et al. 2020

Preprint

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Differentiation of stem cells embedded within the mammary epithelium is orchestrated by lineage-specifying transcription factors. Unlike the well-defined luminal hierarchy, dissection of the basal lineage has been hindered by a lack of specific markers. Inhibitor of Differentiation 4 (ID4) is a basally-restricted helix-loop-helix (HLH) transcription factor essential for mammary development. Here we show that ID4 is highly expressed in basal stem cells and decreases during myoepithelial differentiation. By integrating transcriptomic, proteomic, and ChIP-sequencing data, we reveal that ID4 is required to suppress myoepithelial gene expression and cell fate. We identify the bHLH protein HEB as a direct binding partner of ID4, and describe a previously-unknown role for this regulator in mammary development. HEB binds to E-boxes in regulatory elements of developmental genes, negatively regulated by ID4, involved in extracellular matrix synthesis and cytoskeletal contraction. Together our findings support a model whereby ID4 binds to HEB and blocks it from promoting myoepithelial specialisation. These new insights expand our current understanding into control of myoepithelial differentiation and mammary gland morphogenesis.

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Divergent Matrix-Remodeling Strategies Distinguish Developmental from Neoplastic Mammary Epithelial Cell Invasion Programs

Cited by 57 publications

References 52 publications

Compromised nuclear envelope integrity drives tumor cell invasion

Compromised nuclear envelope integrity drives tumor cell invasion

A pleiotropic role for FGF signaling in mammary gland stromal fibroblasts

Inhibitor of Differentiation 4 (ID4) represses myoepithelial differentiation of mammary stem cells through its interaction with HEB

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