CAF-specific markers: role of the TGFβ pathway.

The predominantly tumorigenic actions of transforming growth factor-beta (TGFβ) in aggressive cancer make the TGFβ pathway an attractive target for therapeutic intervention. Currently a number of TGFβ-targeted cancer therapies are in clinical trials. However, due to the multifaceted role of TGFβ signaling, antagonizing TGFβ in the clinical setting is challenging. Therefore it is essential to develop new predictive tests to account for subtype-specific treatment sensitivities, warranting optimization of more personalized therapeutic strategies. TGFβ is a pleiotropic cytokine with potent antimitogenic and pro-apoptotic effects and is further regulating epithelial-mesenchymal transition (EMT), motility and cell differentiation. Thus, TGFβ signaling plays a key role at multiple steps during tumor progression including invasion, dissemination and metastatic colonization [1]. It is believed that during tumorigenesis a switch from anti-tumorigenic to tumor-promotive actions occurs [2]. However, response toward TGFβ is highly celland context-dependent and consequently in cancer, cellular functions mediated by TGFβ are complex. A TGFβ response signature has been associated with metastatic potential in estrogen receptor-alpha (ERα)negative but not in ERα-positive breast cancer illustrating the need for cancer subtype dependent handling of TGFβ information [2]. Due to the dual function of TGFβ as a tumorsuppressor and tumor-promotor, it is paramount to fully elucidate context-dependent TGFβ-mediated actions and accordingly it is pivotal that the role of critical tumor microenvironmental factors such as the presence and role of cancer-activated fibroblasts (CAFs) is fully understood. TGFβ is a major player in the tumor-stromal crosstalk as it is a known key factor inducing transdifferentiation of fibroblasts into activated fibroblasts, a phenotype that has been linked to CAFs. We and others noted that stromal biomarkers possess clinical value such as CAF-specific Editorial