The extracellular matrix actively influence thyroid cancer cells sensitivity to TKIS

Thyroid cancer (TC) is the most common endocrine tumor and its incidence has increased faster than in any other malignancy. Although TCs are usually well differentiated, disease recurrence or persistence is high, because of local and distant metastasis and therapeutic resistance. As in other cancer types, despite the promising results obtained in pre-clinical studies, the efficacy of Targeted Therapy is highly variable and therapy resistance is not uncommon. This may be due to a lack in the understanding of the complex signaling pathways and feedbacks that cancer cells with a specific genetic background exchange with all the other components of the tumor microenvironments, such as immune cells, fibroblasts, endothelium, and extracellular matrix (ECM). The aim of the present study is to unravel the mechanisms by which cancer associated fibroblasts (CAFs) and ECM can influence the tumor response to different anticancer drugs and to identify new potential druggable pathways. For these purposes, we developed an in vitro model in which a panel of 12 thyroid cancer cell lines with different genetic background is used to activate fibroblast and generate ECMs. The ECMs are then used as culture substrate for the different thyroid cancer cell lines. We used this model to compare how the ECMs produced under different conditions can influence TC cells response to different TKI currently used in clinical practice, such as vemurafenib, lenvatinib and dabrafenib. First, our experiments confirmed that the genetic background of TC cells can significantly influence the degree of activation of CAFs and the type and amount of ECM that they produce. Moreover, the various ECMs differentially influence TC cells growth and their sensitivity to TKIs, irrespectively of their genetic background. These data show that ECM can either actively influence the therapeutic response, and play an active role in the clonal evolution of thyroid cancer, by differentially supporting subpopulations with diverse genetic background. The in vitro modulation of crosstalk between TC cells and fibroblasts may open new perspectives on the complex mechanisms of therapy resistance and eventually allow the development of efficient therapeutic strategies.