Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo

Bruno, Robert D.; Fleming, Jodie M.; George, Andrea L.; Boulanger, Corinne A.; Schedin, Pepper; Smith, Gilbert H.

doi:10.1038/srep40196

Cited by 38 publications

(34 citation statements)

References 35 publications

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“…These serve as early detection methods for breast cancer ( 16 ), the second leading cause of cancer death among women ( 17 ). The ECM influences organization ( 15 ) and differentiation ( 18 , 19 ) of mammary cells into functional mammary structures and tissues. It plays a role in tumor suppression through trafficking of intercellular signals ( 20 ) and exerting physical forces sensed by cell surface proteins, such as integrins ( 10 , 13 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

“…It plays a role in tumor suppression through trafficking of intercellular signals ( 20 ) and exerting physical forces sensed by cell surface proteins, such as integrins ( 10 , 13 , 15 ). Changes in the ECM composition ( 15 , 18 , 19 , 21 ) and stiffness ( 6 – 8 , 15 , 22 , 23 ) have been shown to promote malignant phenotypes. Previous work in the field has investigated the role of ECM in determining cellular response to chemotherapy treatment ( 9 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

et al. 2018

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The persistence of drug resistant cell populations following chemotherapeutic treatment is a significant challenge in the clinical management of cancer. Resistant subpopulations arise via both cell intrinsic and extrinsic mechanisms. Extrinsic factors in the microenvironment, including neighboring cells, glycosaminoglycans, and fibrous proteins impact therapy response. Elevated levels of extracellular fibrous proteins are associated with tumor progression and cause the surrounding tissue to stiffen through changes in structure and composition of the extracellular matrix (ECM). We sought to determine how this progressively stiffening microenvironment affects the sensitivity of breast cancer cells to chemotherapeutic treatment. MDA-MB-231 triple negative breast carcinoma cells cultured in a 3D alginate-based hydrogel system displayed a stiffness-dependent response to the chemotherapeutic doxorubicin. MCF7 breast carcinoma cells cultured in the same conditions did not exhibit this stiffness-dependent resistance to the drug. This differential therapeutic response was coordinated with nuclear translocation of YAP, a marker of mesenchymal differentiation. The stiffness-dependent response was lost when cells were transferred from 3D to monolayer cultures, suggesting that endpoint ECM conditions largely govern the response to doxorubicin. To further examine this response, we utilized a platform capable of dynamic ECM stiffness modulation to allow for a change in matrix stiffness over time. We found that MDA-MB-231 cells have a stiffness-dependent resistance to doxorubicin and that duration of exposure to ECM stiffness is sufficient to modulate this response. These results indicate the need for additional tools to integrate mechanical stiffness with therapeutic response and inform decisions for more effective use of chemotherapeutics in the clinic.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

et al. 2018

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“…Evidence has been provided that mammary ECM can reprogram non-mammary cells to form mammary glands 8,9 , suggesting that it contains critical cues for epithelial development. Hedgehog signaling acts via Gli2 downstream of growth hormone receptor signaling in fibroblasts to trigger changes in paracrine signaling and ECM proteins that affect stem cell function 10 .…”

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confidence: 99%

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

et al. 2020

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Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membranespecific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation.

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“…Instructional interactions between the epithelium and surrounding stroma are well established. This was most exquisitely demonstrated in extensive studies by Smith and colleagues revealing that the local microenvironment of the mammary gland is sufficient to reprogram progenitor cells from completely different tissues (including testicular and embryonic stem cells) into mammary progenitors that were capable of forming normal mammary gland structures [100][101][102][103][104] . Furthermore, alterations in the microenvironment may influence cellular transformation.…”

Section: Implications For Tumor Initiation and Metastasismentioning

confidence: 98%

A new view of the mammary epithelial hierarchy and its implications for breast cancer initiation and metastasis

Anstine

Keri

2019

JCMT

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The existence of mammary epithelial stem cell (MaSC) populations capable of mediating mammary gland development and homeostasis has been established for over a decade. A combination of lineage tracing and mammary gland transplantation studies has affirmed that MaSCs and their downstream progenitors are organized in a hierarchal manner; however, these techniques have failed to illuminate the complete spectrum of epithelial intermediate populations or their spatial and temporal relationships. The advent of single cell sequencing technology has allowed for characterization of highly heterogeneous tissues at high resolution. In the last two years, the remarkable advances in single cell RNA sequencing technologies have been leveraged to address the heterogeneity of the mammary epithelium. These studies have afforded fresh insights into the transcriptional differentiation hierarchy and its chronology. Importantly, these data have led to a major conceptual shift in which the rigid boundaries separating stem, progenitor, and differentiated epithelial populations have been deconstructed, resulting in a new more fluid and flexible model of epithelial differentiation. The emerging view of the mammary epithelial hierarchy has important implications for mammary development, carcinogenesis, and metastasis, providing novel insights into the underlying cellular states that may promote malignant phenotypes.

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Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo

Cited by 38 publications

References 35 publications

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

Phenotypic Basis for Matrix Stiffness-Dependent Chemoresistance of Breast Cancer Cells to Doxorubicin

The secreted protease Adamts18 links hormone action to activation of the mammary stem cell niche

A new view of the mammary epithelial hierarchy and its implications for breast cancer initiation and metastasis

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