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Integrin-Piezo1 Axis Drives ECM Remodeling and Invasion of 3D Breast Epithelium

Sakthivel, Kabilan LU orcid ; Kotowska, Anna ; Fan, Zhimeng LU ; Portner, Ellen Juel ; Merry, Catherine ; Nordenfelt, Pontus LU orcid ; Simonsen, Adam Cohen ; Wright, Amanda J. and Swaminathan, Vinay S. LU orcid (2025) In Advanced Science
Abstract

Stiffening of tissue is a hallmark of cancer progression, promoting invasive phenotypes through altered cell-extracellular matrix (ECM) interactions. However, how fully formed epithelial structures respond to mechanical cues within their native ECM environment remains poorly understood. Here, using a 3D in situ stiffening hydrogel system that enables modulation of stiffness around mature normal mammary acini, it uncovers critical steps in ECM remodeling and invasion of epithelial structures and discover molecular mechanisms driving this process. Stiffening around mature acini triggers two temporally distinct phases of epithelial remodeling, a rapid priming phase involving basement membrane (laminin, LN) disruption and fibronectin (FN)... (More)

Stiffening of tissue is a hallmark of cancer progression, promoting invasive phenotypes through altered cell-extracellular matrix (ECM) interactions. However, how fully formed epithelial structures respond to mechanical cues within their native ECM environment remains poorly understood. Here, using a 3D in situ stiffening hydrogel system that enables modulation of stiffness around mature normal mammary acini, it uncovers critical steps in ECM remodeling and invasion of epithelial structures and discover molecular mechanisms driving this process. Stiffening around mature acini triggers two temporally distinct phases of epithelial remodeling, a rapid priming phase involving basement membrane (laminin, LN) disruption and fibronectin (FN) secretion, followed by a delayed invasion phase characterized by FN remodeling and LN re-deposition that coincides with acinar proliferation and invasion. Mechanistically, it is shown that these changes are mediated by α3β1- and α5β1-integrin–focal adhesion kinase (FAK) signaling, which in turn activates the mechanosensitive ion channel Piezo1 to regulate ECM composition, remodeling, and acinar invasion. Together, the findings reveal how mature epithelial structures dynamically respond to mechanical stiffening to create an invasive niche, offering new insights into how tissue architecture and stiffness synergize to drive breast cancer progression.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
3D Mechanotransduction, ECM remodeling, Integrin signaling, Mammary acini, Stretch activated channels
in
Advanced Science
article number
e09932
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:41082347
  • scopus:105018720198
ISSN
2198-3844
DOI
10.1002/advs.202509932
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.
id
0683831a-7f9e-4878-99a9-6793fead27b4
date added to LUP
2026-01-22 15:01:57
date last changed
2026-01-23 09:36:06
@article{0683831a-7f9e-4878-99a9-6793fead27b4,
  abstract     = {{<p>Stiffening of tissue is a hallmark of cancer progression, promoting invasive phenotypes through altered cell-extracellular matrix (ECM) interactions. However, how fully formed epithelial structures respond to mechanical cues within their native ECM environment remains poorly understood. Here, using a 3D in situ stiffening hydrogel system that enables modulation of stiffness around mature normal mammary acini, it uncovers critical steps in ECM remodeling and invasion of epithelial structures and discover molecular mechanisms driving this process. Stiffening around mature acini triggers two temporally distinct phases of epithelial remodeling, a rapid priming phase involving basement membrane (laminin, LN) disruption and fibronectin (FN) secretion, followed by a delayed invasion phase characterized by FN remodeling and LN re-deposition that coincides with acinar proliferation and invasion. Mechanistically, it is shown that these changes are mediated by α3β1- and α5β1-integrin–focal adhesion kinase (FAK) signaling, which in turn activates the mechanosensitive ion channel Piezo1 to regulate ECM composition, remodeling, and acinar invasion. Together, the findings reveal how mature epithelial structures dynamically respond to mechanical stiffening to create an invasive niche, offering new insights into how tissue architecture and stiffness synergize to drive breast cancer progression.</p>}},
  author       = {{Sakthivel, Kabilan and Kotowska, Anna and Fan, Zhimeng and Portner, Ellen Juel and Merry, Catherine and Nordenfelt, Pontus and Simonsen, Adam Cohen and Wright, Amanda J. and Swaminathan, Vinay S.}},
  issn         = {{2198-3844}},
  keywords     = {{3D Mechanotransduction; ECM remodeling; Integrin signaling; Mammary acini; Stretch activated channels}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Advanced Science}},
  title        = {{Integrin-Piezo1 Axis Drives ECM Remodeling and Invasion of 3D Breast Epithelium}},
  url          = {{http://dx.doi.org/10.1002/advs.202509932}},
  doi          = {{10.1002/advs.202509932}},
  year         = {{2025}},
}