Abstract
Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome.
Highlights
Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease
In concordance with the histological data (Fig. 1a), we show that aggressive 4T1 tumours contain a significantly higher proportion of CAFs (GFP þ ; CD45 À cells) as compared with the less aggressive 4T07 tumours (Fig. 1b). qPCR analysis of fibroblast populations confirmed that CAFs from more aggressive breast tumours have an ‘activated’ CAF phenotype as evidenced by the gradient increase in expression of the myofibroblast markers aSMA (Acta2)[2], transgelin (Tagln)[18] and TGFb1 (Tgfb1)[19,20,21] from control mouse mammary gland fibroblasts (MGFs) to 4T07 fibroblasts to 410.4/4T1 fibroblasts (Fig. 1c)
We demonstrate that the 4T1 tumour cell line series recapitulates human disease in showing a strong correlation between a desmoplastic response and tumour aggressiveness, and making it a valid model for studying heterogeneity of the CAF compartment in vivo
Summary
Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. There is extensive evidence functionally implicating CAFs in tumour progression via their ability to deposit and remodel extracellular matrix components, secrete pro-tumorigenic factors and modulate the immune compartment[1,2,3,4,5] In breast cancer this so-called ‘desmoplastic response’ shows a clinical correlation with invasion and poor patient prognosis[6]. Despite the growing interest in the functional role of CAFs in tumours, much of their biology remains a mystery because of the lack of specific markers, as well as fibroblast phenotypic plasticity and heterogeneity both in vivo and in vitro[8,9] Together, these have hampered efforts to disentangle the mechanisms underlying tumour:fibroblast crosstalk that could reveal novel strategies for disrupting stromal activation and thereby enhancing therapeutic targeting of tumour cells. We identify a novel level of interaction between Wnt and TGFb pathways in CAFs, which presents a potential avenue for inhibiting or reversing the production of a tumour-promoting stroma
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