Tumor:fibroblast crosstalk mechanism to promote cancer aggressiveness

Tumor:fibroblast crosstalk mechanism to promote cancer aggressiveness

Fibroblasts constitute a significant proportion of the stromal compartment in many solid tumors and these infiltrating cells can acquire an activated cancer-associated fibroblast (CAF) phenotype. There is now extensive evidence functionally implicating CAFs in tumor progression via their ability to deposit and remodel extracellular matrix components, secrete pro-tumorigenic factors and modulate the immune compartment.

In breast cancer this so-called ‘desmoplastic response’ shows a clinical correlation with invasion and poor patient prognosis. In addition, there is an increasing body of data supporting a role of CAFs in promoting resistance to chemotherapy and targeted agents.

Despite the growing interest in the functional role of CAFs in tumors, 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.

Together, these have hampered efforts to disentangle the mechanisms underlying tumor:fibroblast crosstalk that could reveal novel strategies for disrupting stromal activation and thereby enhancing therapeutic targeting of tumor cells.

Using in vivo models researchers identify Wnt7a as a key factor secreted exclusively by aggressive breast tumor cells, which induces CAF conversion.

Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumor cell invasion and promotion of distant metastasis.

Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, authors 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, tumor cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome.