Notch signalling mediates myofibroblast differentiation of carcinoma-associated fibroblasts


Session type:

Ahmet Acar1,2, Göran Landberg2, Akira Orimo1
1CR-UK Stromal-Tumour Interaction Group, Paterson Institute for Cancer Research, Manchester, UK, 2Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Researc, Manchester, UK


Carcinoma-associated fibroblasts (CAFs) consist of large proportions of myofibroblasts, a hallmark of activated fibroblasts often found in wound healing and fibrosis. The tissue remodelling processes involved in wound healing and fibrosis physiologically resemble those occurring within the tumour-associated stroma. Given crucial roles of Notch signalling for promoting myofibroblast differentiation during the tissue remodelling, we hypothesized that activation of this signalling pathway may contribute to give rise to CAFs in the tumour-associated stroma


We recently developed human immortalised breast CAFs, designated experimentally generated CAFs (exp-CAFs), by extracting them from human mammary tumour xenografts1. Using exp-CAFs, we examined the expression levels of various Notch signalling components by Western blot and qRT-PCR analyses.


Here we show that these cells express increased levels of Notch ligands Jagged1 (Jag1) and Delta-like 4 (Dll4), and their receptors (Notch 1-3). These Notch ligands present on the signal-sending CAFs are also required for transactivation of Notch3 expressed on the signal-receiving CAFs. Importantly, this ligand-activated Notch3 stimulates the canonical Notch signalling, as exemplified by increased expression of Hes-1 and Notch intracellular domain 3 (NICD3). Activation of Notch signalling also collaborates with TGF-b signalling to further boost myofibroblast differentiation in CAFs. Moreover, immunohistochemistry reveals that stromal myofibroblasts within human invasive breast carcinomas are positively stained for Jag1, Dll4, and NICD3.


Collectively, these findings suggest that both Notch and TGF-b signalling are crucial for generation and maintenance of myofibroblasts within the tumour-associated stroma.