Mellone, Massimiliano, Hanley, Christopher J, Thirdborough, Steve, Mellows, Toby, Garcia, Edwin, Woo, Jeongmin, Tod, Joanne, Frampton, Steve, Jenei, Veronika, Moutasim, Karwan A et al (show 17 more authors)
(2017)
Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis.
AGING-US, 9 (1).
pp. 128-146.
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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 <i>ex vivo</i>, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. <i>In vitro</i>, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | tumor microenvironment, myofibroblasts, senescence, collagen, extracellular matrix, senescent fibroblasts |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 19 Apr 2023 09:22 |
| Last Modified: | 19 Apr 2023 09:22 |
| DOI: | 10.18632/aging.101127 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169671 |
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