Co-culture of cancer cells (darker cells) with stromal fibroblasts (lighter cells) with a signalling molecule shown in green speckles.

Introduction

Within the tumour microenvironment, cancer-associated fibroblasts (CAFs) provide a chemical and physical environment that favours tumour aggressiveness and dissemination.

Thus, targeting CAFs represents an interesting alternative for therapeutic intervention to halt tumour progression.

Our group is focused on trying to understand why and how cancer cells spread through the body. In particular, we are interested in the role of stromal cells within the tumour and how cancer cells move through the extensively remodelled tumour extra-cellular matrix. Within the tumour microenvironment, cancer-associated fibroblasts (CAFs) provide a chemical and physical environment that favours tumour aggressiveness and dissemination. Thus, targeting CAFs represents an interesting alternative for therapeutic intervention to halt tumour progression.

To learn more about CAFs, Fernando Calvo isolated fibroblasts from different stages of breast cancer progression and analysed their function and gene expression. These analyses reveal that activation of the YAP transcription factor is a signature feature of CAFs. YAP function is required for CAFs to promote matrix stiffening, cancer cell invasion and angiogenesis. Matrix stiffening further enhances YAP activation, thus establishing a feed-forward loop. Once this feedback is established it can become self-sustaining, and this could explain the stability of the CAF phenotype in the absence cancer cells.

We also observed that actomyosin contractility and Src function are required for YAP activation by stiff matrices. Interestingly, Nil Ege was able to show that transient ROCK inhibition was able to disrupt the feed-forward loop, leading to a long-lasting reversion of the CAF phenotype.