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Decoding the Matrix: Multiscale Mechanosensing and Mechanical Memory in Fibroblasts

Packirisamy, Swathi LU orcid (2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Cancer progression is profoundly influenced by the dynamic interactions between cancer cells and their surrounding tumour microenvironment (TME). A defining feature of the TME is the progressive remodelling of the extracellular matrix (ECM), which becomes stiffer and structurally altered during disease progression. These changes regulate cell behaviour and contribute to tumour growth, invasion and metastasis. Fibroblasts are central mediators of this process, sensing ECM mechanics through integrin-based focal adhesions (FAs) and responding by altering their activation state and remodelling the surrounding matrix. Increasing evidence suggests that fibroblasts can acquire mechanical memory and remain active even after the initiating... (More)
Cancer progression is profoundly influenced by the dynamic interactions between cancer cells and their surrounding tumour microenvironment (TME). A defining feature of the TME is the progressive remodelling of the extracellular matrix (ECM), which becomes stiffer and structurally altered during disease progression. These changes regulate cell behaviour and contribute to tumour growth, invasion and metastasis. Fibroblasts are central mediators of this process, sensing ECM mechanics through integrin-based focal adhesions (FAs) and responding by altering their activation state and remodelling the surrounding matrix. Increasing evidence suggests that fibroblasts can acquire mechanical memory and remain active even after the initiating mechanical stimulus has been removed, driving pathological ECM remodelling and disease progression. However, the exact molecular mechanisms by which fibroblasts sense the ECM and become persistently activated remain poorly understood.
The aim of this thesis was to investigate how fibroblasts sense the mechanical properties of the ECM and how mechanosensing is coupled to persistent fibroblast activation. Using cell biology, imaging, computational modelling and molecular approaches, this work demonstrates that the nanoscale organization of FA components is a key regulator of mechanosensing and identifies septin-7 as a spatial regulator of FA maturation. Furthermore, it shows that integrin-mediated ECM sensing is linked to chromatin remodelling, providing a mechanistic basis for the establishment of persistent fibroblast activation through mechanical memory.
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author
supervisor
opponent
  • Dr Miroshnikova, Yekaterina, Max Planck Institute
organization
publishing date
type
Thesis
publication status
published
subject
keywords
extracellular matrix, fibroblast, cancer associated fibroblasts, Mechanosensing, integrins, focal adhesions, mechanical memory
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2026:103
pages
91 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
defense date
2026-09-10 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-901-3
language
English
LU publication?
yes
id
948d4cb5-4a4a-4380-946f-492e3b7021e3
date added to LUP
2026-08-17 10:53:53
date last changed
2026-08-26 12:22:35
@phdthesis{948d4cb5-4a4a-4380-946f-492e3b7021e3,
  abstract     = {{Cancer progression is profoundly influenced by the dynamic interactions between cancer cells and their surrounding tumour microenvironment (TME). A defining feature of the TME is the progressive remodelling of the extracellular matrix (ECM), which becomes stiffer and structurally altered during disease progression. These changes regulate cell behaviour and contribute to tumour growth, invasion and metastasis. Fibroblasts are central mediators of this process, sensing ECM mechanics through integrin-based focal adhesions (FAs) and responding by altering their activation state and remodelling the surrounding matrix. Increasing evidence suggests that fibroblasts can acquire mechanical memory and remain active even after the initiating mechanical stimulus has been removed, driving pathological ECM remodelling and disease progression. However, the exact molecular mechanisms by which fibroblasts sense the ECM and become persistently activated remain poorly understood.  <br/>The aim of this thesis was to investigate how fibroblasts sense the mechanical properties of the ECM and how mechanosensing is coupled to persistent fibroblast activation. Using cell biology, imaging, computational modelling and molecular approaches, this work demonstrates that the nanoscale organization of FA components is a key regulator of mechanosensing and identifies septin-7 as a spatial regulator of FA maturation. Furthermore, it shows that integrin-mediated ECM sensing is linked to chromatin remodelling, providing a mechanistic basis for the establishment of persistent fibroblast activation through mechanical memory. <br/>}},
  author       = {{Packirisamy, Swathi}},
  isbn         = {{978-91-8021-901-3}},
  issn         = {{1652-8220}},
  keywords     = {{extracellular matrix; fibroblast; cancer associated fibroblasts; Mechanosensing; integrins; focal adhesions; mechanical memory}},
  language     = {{eng}},
  number       = {{2026:103}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Decoding the Matrix: Multiscale Mechanosensing and Mechanical Memory in Fibroblasts}},
  url          = {{https://lup.lub.lu.se/search/files/258253459/enailing_Swathi.pdf}},
  year         = {{2026}},
}