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

Author

Listed:
  • Koen Schipper

    (The Netherlands Cancer Institute)

  • Danielle Seinstra

    (The Netherlands Cancer Institute)

  • Anne Paulien Drenth

    (The Netherlands Cancer Institute)

  • Eline Burg

    (The Netherlands Cancer Institute)

  • Veronika Ramovs

    (The Netherlands Cancer Institute)

  • Arnoud Sonnenberg

    (The Netherlands Cancer Institute)

  • Jacco Rheenen

    (The Netherlands Cancer Institute)

  • Micha Nethe

    (The Netherlands Cancer Institute
    Academic Medical Center)

  • Jos Jonkers

    (The Netherlands Cancer Institute)

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.

Suggested Citation

  • Koen Schipper & Danielle Seinstra & Anne Paulien Drenth & Eline Burg & Veronika Ramovs & Arnoud Sonnenberg & Jacco Rheenen & Micha Nethe & Jos Jonkers, 2019. "Rebalancing of actomyosin contractility enables mammary tumor formation upon loss of E-cadherin," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11716-6
    DOI: 10.1038/s41467-019-11716-6
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    Cited by:

    1. Amanda Fitzpatrick & Marjan Iravani & Adam Mills & David Vicente & Thanussuyah Alaguthurai & Ioannis Roxanis & Nicholas C. Turner & Syed Haider & Andrew N. J. Tutt & Clare M. Isacke, 2023. "Genomic profiling and pre-clinical modelling of breast cancer leptomeningeal metastasis reveals acquisition of a lobular-like phenotype," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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