Dataset Information

Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin.

ABSTRACT: E-cadherin (CDH1) is a master regulator of epithelial cell adherence junctions and a well-established tumor suppressor in Invasive Lobular Carcinoma (ILC). Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation. Here we show that E-cadherin loss induces extrusion of luminal MMECs to the basal lamina. Remarkably, E-cadherin-deficient MMECs can breach the basal lamina but do not disseminate into the surrounding fat pad. Basal lamina components laminin and collagen IV supported adhesion and survival of E-cadherin-deficient MMECs while collagen I, the principle component of the mammary stromal micro-environment did not. We uncovered that relaxation of actomyosin contractility mediates adhesion and survival of E-cadherin-deficient MMECs on collagen I, thereby allowing ILC development. Together, these findings unmask the direct consequences of E-cadherin inactivation in the mammary gland and identify aberrant actomyosin contractility as a critical barrier to ILC formation.

SUBMITTER: Schipper K

PROVIDER: S-EPMC6707221 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin.

Schipper Koen K Seinstra Danielle D Paulien Drenth Anne A van der Burg Eline E Ramovs Veronika V Sonnenberg Arnoud A van Rheenen Jacco J Nethe Micha M Jonkers Jos J

Nature communications 20190823 1

E-cadherin (CDH1) is a master regulator of epithelial cell adherence junctions and a well-established tumor suppressor in Invasive Lobular Carcinoma (ILC). Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation. Here we show that E-cadherin loss induces extrusion of luminal MMECs to the basal lamina. Remarkably, E-cadherin-deficient MMECs can breach the basal lamina but do not disseminate into the surrounding fat ...[more]

PMID: 31444332

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Project description:Neuronal nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central and peripheral nervous system and are localized at synaptic and extrasynaptic sites of the cell membrane. However, the mechanisms regulating the localization of nicotinic receptors in distinct domains of the cell membrane are not well understood. N-cadherin is a cell adhesion molecule that mediates homotypic binding between apposed cell membranes and regulates the actin cytoskeleton through protein interactions with the cytoplasmic domain. At synaptic contacts, N-cadherin is commonly localized adjacent to the active zone and the postsynaptic density, suggesting that N-cadherin contributes to the assembly of the synaptic complex. To examine whether N-cadherin homotypic binding regulates the cell surface localization of nicotinic receptors, this study used heterologous expression of N-cadherin and ?3?4 nAChR subunits C-terminally fused to a myc-tag epitope in Chinese hamster ovary cells. Expression levels of ?3?4 nAChRs at cell-cell contacts and at contact-free cell membrane were analyzed by confocal microscopy. ?3?4 nAChRs were found distributed over the entire surface of contacting cells lacking N-cadherin. In contrast, N-cadherin-mediated cell-cell contacts were devoid of ?3?4 nAChRs. Cell-cell contacts mediated by N-cadherin-deleted proteins lacking the ?-catenin binding region or the entire cytoplasmic domain showed control levels of ?3?4 nAChRs expression. Inhibition of actin polymerization with latrunculin A and cytochalasin D did not affect ?3?4 nAChRs localization within N-cadherin-mediated cell-cell contacts. However, treatment with the Rho associated kinase inhibitor Y27632 resulted in a significant increase in ?3?4 nAChR levels within N-cadherin-mediated cell-cell contacts. Analysis of ?3?4 nAChRs localization in polarized Caco-2 cells showed specific expression on the apical cell membrane and colocalization with apical F-actin and the actin nucleator Arp3. These results indicate that actomyosin contractility downstream of N-cadherin homotypic binding regulates the cell surface localization of ?3?4 nAChRs presumably through interactions with a particular pool of F-actin.

Dataset Information

Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin.

Publications

Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin.

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