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

Schipper, Koen; Seinstra, Daniëlle; Drenth, Anne Paulien; Burg, Eline van der; Ramovs, Veronika; Sonnenberg, Arnoud; Rheenen, Jacco van; Nethe, Micha; Jonkers, Jos

doi:10.1038/s41467-019-11716-6

Cited by 25 publications

(34 citation statements)

References 61 publications

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“…This speaks to the different propagation mode of the lobular cells, which rely on their home‐made matrix for proliferation and migration and likely reflects very different interactions with the host's mammary epithelium. The observation that ILC cells home to ductal tips within the mouse milk duct system suggests that these cells are particularly motile and begs the question whether the multifocality characteristic to lobular disease is not a field cancerization phenomenon (Dotto, 2014) but attributable to migration of tumor cells within the ductal tree (Lee et al , 2019; Schipper et al , 2019).…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…The MYPT1 and ASPP2 truncation variants both retain their PP1 binding motif indicating that this interaction might be important for their ability to induce ILC. In addition, both MYPT1 and ASPP2 truncation variants lack negative regulatory domains indicating that these truncations are dominant-active variants (5,22,23). We found that expression of truncated MYPT1 and inhibition of MYH9 induces ILC formation by reducing actomyosin contractility in E-cadherin-deficient murine mammary epithelial cells (MMECs) (5).…”

Section: Introductionmentioning

confidence: 89%

“…In addition, both MYPT1 and ASPP2 truncation variants lack negative regulatory domains indicating that these truncations are dominant-active variants (5,22,23). We found that expression of truncated MYPT1 and inhibition of MYH9 induces ILC formation by reducing actomyosin contractility in E-cadherin-deficient murine mammary epithelial cells (MMECs) (5). Reduction of actomyosin contraction enables E-cadherin-deficient MMECs to adhere and grow on stiff matrixes like fibrillar collagen (5).…”

Section: Introductionmentioning

confidence: 91%

“…ILCs typically display a discohesive morphology caused by functional loss of the intercellular adhesion protein E-cadherin (encoded by CDH1) (4). Loss of E-cadherin in mammary epithelium drives cell extrusion of luminal epithelial cells into the surrounding mammary stroma and underlies the strong infiltrative nature of ILC (5). The highly infiltrative nature of ILCs typically complicates early detection and surgical removal (6).…”

Section: Introductionmentioning

confidence: 99%

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Truncated ASPP2 Drives Initiation and Progression of Invasive Lobular Carcinoma via Distinct Mechanisms

et al. 2020

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Invasive lobular carcinoma (ILC) accounts for 8-14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell-cell adhesion protein E-cadherin.Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development indicating that additional perturbations are required for ILC formation.Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin-deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1 (PP1) but not on t-ASPP2-induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2-induced actomyosin relaxation was required for ILC initiation but not progression. Conversely, YAP1 activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression. Statement of significanceTruncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation while ASPP2-mediated YAP1 activation enhances tumor progression.

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“…The extruded E-cadherin-deficient cells showed increased levels of phospho-myosin light chain and non-apoptotic membrane blebbing. Reduction of contractility resulted in increased survival and proliferation, as well as the development of invasive lobular carcinoma [87].…”

Section: Pressures Driving Migration: Cell Crowding and Unbalanced Mementioning

confidence: 99%

The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis

Nikolaou

Machesky

2020

The Journal of Pathology

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Tumours evolve to cope with environmental stresses or challenges such as nutrient starvation, depletion of survival factors, and unbalanced mechanical forces. The uncontrolled growth and aberrant deregulation of core cell homeostatic pathways induced by genetic mutations create an environment of stress. Here, we explore how the adaptations of tumours to the changing environment can drive changes in the motility machinery of cells, affecting migration, invasion, and metastasis. Tumour cells can invade individually or collectively, or they can be extruded out of the surrounding epithelium. These mechanisms are thought to be modifications of normal processes occurring during development or tissue repair. Therefore, tumours may activate these pathways in response to environmental stresses, enabling them to survive in hostile environments and spread to distant sites.

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

Cited by 25 publications

References 61 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

Truncated ASPP2 Drives Initiation and Progression of Invasive Lobular Carcinoma via Distinct Mechanisms

The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis

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