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

Ataca, Dalya; Aouad, Patrick; Constantin, Céline; László, Csaba; Beleut, Manfred; Shamseddin, Marie; Rajaram, R; Jeitziner, Rachel; Mead, Timothy J.; Caikovski, Marian; Bücher, Philipp; Ambrosini, Giovanna; Apte, Suneel S.; Brisken, Cathrin

doi:10.1038/s41467-020-15357-y

Cited by 41 publications

(40 citation statements)

References 68 publications

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“…Given that only tumor cell-derived RNAs were taken into account, it was surprising to observe that extracellular matrix (ECM) organization ranked as the most enriched gene signature ( Fig 3C). Next to collagen type VI alpha 2 chain (COL6A2), laminin subunits (LAMA1 and LAMA4) were multiple proteases like matrix metallopeptidase 7 (MMP7), cathepsin V (CTSV), and several ADAM metallopeptidase with thrombospondin type 1 motif 1 members including ADAMTS18, recently shown to be important for mammary stem cell function (Ataca et al, 2020) (Fig 3D, E). Interestingly, among the most highly upregulated genes were the luminal progenitor marker CKIT (Appendix Fig S1D) and the stem cell marker ALDH1A3 (Marcato et al, 2011).…”

Section: Molecular Characteristics Of Ilc Pdxsmentioning

confidence: 99%

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

et al. 2021

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Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC‐derived breast cancer cell lines, SUM‐44 PE and MDA‐MB‐134‐VI cells, into the mouse milk ducts. Using patient‐derived intraductal xenografts from lobular and non‐lobular ER+ HER2− tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell‐intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC.

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Section: Molecular Characteristics Of Ilc Pdxsmentioning

confidence: 99%

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

et al. 2021

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“…This possibility was further indicated by the finding that ADAMTS18 regulates mammary stem cell niche by cleaving fibronectin. This action may lead to changes in the abundance of collagen I, collagen IV, laminin, and collagen XVIII ( Ataca et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

ADAMTS18 Deficiency Leads to Pulmonary Hypoplasia and Bronchial Microfibril Accumulation

Lin

Pan

et al. 2020

iScience

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Summary ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18- deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis.

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“…130-104-694) was used to enrich the digest for PCa human cells by depleting murine cell populations including fibroblasts, immune cells, and endothelial cells from the PDX digests. Previous studies have used this kit for similar applications 31 , 32 . Approximately 5 × 10 7 dissociated PDX cells were resuspended with 80 µL of cold separation buffer (0.5% BSA, 100 U/mL PenStrep in PBS) and 20 µL of Mouse Cell Depletion cocktail, and then incubated for 15 min at 4 °C, with occasional agitation.…”

Section: Methodsmentioning

confidence: 99%

Using the Microwell-mesh to culture microtissues in vitro and as a carrier to implant microtissues in vivo into mice

Monterosso

Futrega

Lott

et al. 2021

Sci Rep

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Prostate cancer (PCa) patient-derived xenografts (PDXs) are commonly propagated by serial transplantation of “pieces” of tumour in mice, but the cellular composition of pieces is not standardised. Herein, we optimised a microwell platform, the Microwell-mesh, to aggregate precise numbers of cells into arrays of microtissues, and then implanted the Microwell-mesh into NOD-scid IL2γ−/− (NSG) mice to study microtissue growth. First, mesh pore size was optimised using microtissues assembled from bone marrow-derived stromal cells, with mesh opening dimensions of 100×100 μm achieving superior microtissue vascularisation relative to mesh with 36×36 μm mesh openings. The optimised Microwell-mesh was used to assemble and implant PCa cell microtissue arrays (hereafter microtissues formed from cancer cells are referred to as microtumours) into mice. PCa cells were enriched from three different PDX lines, LuCaP35, LuCaP141, and BM18. 3D microtumours showed greater in vitro viability than 2D cultures, but neither proliferated. Microtumours were successfully established in mice 81% (57 of 70), 67% (4 of 6), 76% (19 of 25) for LuCaP35, LuCaP141, and BM18 PCa cells, respectively. Microtumour growth was tracked using live animal imaging for size or bioluminescence signal. If augmented with further imaging advances and cell bar coding, this microtumour model could enable greater resolution of PCa PDX drug response, and lead to the more efficient use of animals. The concept of microtissue assembly in the Microwell-mesh, and implantation in vivo may also have utility in implantation of islets, hair follicles or other organ-specific cells that self-assemble into 3D structures, providing an important bridge between in vitro assembly of mini-organs and in vivo implantation.

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

Cited by 41 publications

References 68 publications

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

ADAMTS18 Deficiency Leads to Pulmonary Hypoplasia and Bronchial Microfibril Accumulation

Using the Microwell-mesh to culture microtissues in vitro and as a carrier to implant microtissues in vivo into mice

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