期刊
AGING-US
卷 9, 期 1, 页码 128-146出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.101127
关键词
tumor microenvironment; myofibroblasts; senescence; collagen; extracellular matrix; senescent fibroblasts
资金
- Cancer Research UK [C21825/A13315]
- Health Foundation [6467/2835]
- British Association of Oral and Maxillofacial Surgeons
- Wessex Medical Research [S07]
- GlaxoSmithKline
- Academy of Medical Sciences (AMS) [AMS-SGCL12-Moutasim] Funding Source: researchfish
- Cancer Research UK [15951, 22795, 20613] Funding Source: researchfish
- Medical Research Council [MC_U120085810, G1002565, 1641489] Funding Source: researchfish
- National Institute for Health Research [CL-2011-26-003] Funding Source: researchfish
- Versus Arthritis [18892] Funding Source: researchfish
- MRC [MC_U120085810] Funding Source: UKRI
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD016262] Funding Source: NIH RePORTER
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-beta signaling. Similar to TGF-beta 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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