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-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.
Highlights
Cancer-associated fibroblasts (CAF) have been shown to promote many, if not all, of the ‘hallmarks of malignancy’ [1]
The importance of smooth muscle actin (SMA)-positive CAF in tumor progression is highlighted by the poor survival rates of patients with this type of tumor stroma, with contractile cells likely to actively contribute to tumor progression through generating increased tissue tension and promoting tumor cell mechanotransduction, invasion and metastasis [11,12,13, 38, 39]
The degree of in vitro myofibroblast contractility has been shown to correlate with tumor promotion in vivo [2], and studies using 3D model systems have shown that mechanical remodelling of the extracellular matrix (ECM) through cellular contraction is a requirement for cancer cell invasion [8, 39]
Summary
Cancer-associated fibroblasts (CAF) have been shown to promote many, if not all, of the ‘hallmarks of malignancy’ [1]. Despite their tumor-promoting properties, CAF remain a poorly-defined, heterogeneous cell population, possibly reflecting their cell(s) of origin, the tissue in which they develop, and their activation state [1,2,3]. The motility-promoting effects of myofibroblasts result, at least in part, from their contractility and remodeling of collagenous extracellular matrix (ECM) proteins, which serves to generate tissue tension and increased matrix stiffness [5, 11]. Recent studies have shown that there is a significant degree of heterogeneity in how CAFs interact with the ECM which influences disease progression [15, 16]
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