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Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis

Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis
Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-? signaling. Similar to TGF-?1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
1945-4589
114
Mellone, Massimiliano
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Hanley, Christopher
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Thirdborough, Stephen
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Mellows, Toby
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Garcia, Edwin
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Woo, Jeongmin
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Tod, Joanne
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Frampton, Steven
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Jenei, Veronika
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Moutasim, Karwan
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Kabir, Tasnuva D.
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Brennan, Peter A
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Venturi, Giulia
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Ford, Kirsty
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Herranz, Nicolas
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Lim, Kue Peng
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Clarke, James
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Lambert, Daniel W.
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Prime, Stephen S.
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Underwood, Timothy J.
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Vijayanand, Pandurangan
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Eliceiri, Kevin W.
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Woelk, Christopher
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King, Emma
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Gil, Jesus
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Ottensmeier, Christian
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Thomas, Gareth
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Mellone, Massimiliano
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Hanley, Christopher
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Thirdborough, Stephen
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Mellows, Toby
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Garcia, Edwin
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Woo, Jeongmin
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Tod, Joanne
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Frampton, Steven
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Jenei, Veronika
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Moutasim, Karwan
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Kabir, Tasnuva D.
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Brennan, Peter A
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Venturi, Giulia
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Ford, Kirsty
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Herranz, Nicolas
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Lim, Kue Peng
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Clarke, James
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Lambert, Daniel W.
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Prime, Stephen S.
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Underwood, Timothy J.
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Vijayanand, Pandurangan
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Eliceiri, Kevin W.
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Woelk, Christopher
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King, Emma
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Gil, Jesus
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Ottensmeier, Christian
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Thomas, Gareth
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Mellone, Massimiliano, Hanley, Christopher, Thirdborough, Stephen, Mellows, Toby, Garcia, Edwin, Woo, Jeongmin, Tod, Joanne, Frampton, Steven, Jenei, Veronika, Moutasim, Karwan, Kabir, Tasnuva D., Brennan, Peter A, Venturi, Giulia, Ford, Kirsty, Herranz, Nicolas, Lim, Kue Peng, Clarke, James, Lambert, Daniel W., Prime, Stephen S., Underwood, Timothy J., Vijayanand, Pandurangan, Eliceiri, Kevin W., Woelk, Christopher, King, Emma, Gil, Jesus, Ottensmeier, Christian and Thomas, Gareth (2016) Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis. Aging, 9 (1), 114. (doi:10.18632/aging.101127). (PMID:27992856)

Record type: Article

Abstract

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-? signaling. Similar to TGF-?1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.

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Submitted date: 10 August 2016
Accepted/In Press date: 29 November 2016
e-pub ahead of print date: 15 December 2016
Published date: 15 December 2016
Organisations: Cancer Sciences, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 404869
URI: https://eprints.soton.ac.uk/id/eprint/404869
ISSN: 1945-4589
PURE UUID: c60b8db2-fb2a-4a3e-b56a-7171a43e8c36
ORCID for Massimiliano Mellone: ORCID iD orcid.org/0000-0002-4964-9340
ORCID for Christopher Hanley: ORCID iD orcid.org/0000-0003-3816-7220
ORCID for Timothy J. Underwood: ORCID iD orcid.org/0000-0001-9455-2188

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Date deposited: 24 Jan 2017 14:29
Last modified: 10 Dec 2019 01:46

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Contributors

Author: Massimiliano Mellone ORCID iD
Author: Christopher Hanley ORCID iD
Author: Toby Mellows
Author: Edwin Garcia
Author: Jeongmin Woo
Author: Joanne Tod
Author: Steven Frampton
Author: Veronika Jenei
Author: Karwan Moutasim
Author: Tasnuva D. Kabir
Author: Peter A Brennan
Author: Giulia Venturi
Author: Kirsty Ford
Author: Nicolas Herranz
Author: Kue Peng Lim
Author: James Clarke
Author: Daniel W. Lambert
Author: Stephen S. Prime
Author: Pandurangan Vijayanand
Author: Kevin W. Eliceiri
Author: Emma King
Author: Jesus Gil
Author: Gareth Thomas

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