Investigating the role of ADAM17 in the crosstalk between cancer associated fibroblasts and cancer cells

Background: Cancer associated fibroblasts (CAFs) promote cancer progression. Moreover, upregulation of a disintegrin and metalloproteinases (ADAMs) can foster cancer growth and invasion in diverse malignancies. ADAM17, which modulates over 80 substrates including many involved in tumour progression, can be upregulated in CAFs. Hence, a better understanding of the role of ADAM17 in CAFs may help identify novel mechanisms driving CAF-mediated cancer progression and new therapeutic targets. Aims: This project aimed to assess the role of ADAM17 in interactions between CAFs and cancer cells. It was investigated whether cancer cells programme CAFs to release pro-migratory factors through the activation of the CAF-associated ADAM17. Approach: Normal Oral Fibroblasts (NOFs) and CAFs were stimulated with the conditioned medium (C.M.) derived from oral squamous cell carcinoma (OSCC) cell lines and ADAM17 expression was determined. Next, ADAM17 was genetically silenced in NOFs and CAFs gene expression changes identified using proteomics. Thereafter, cancer cells were cultured with the C.M. derived from ADAM17-deficient CAFs to determine their impact on cancer cell migration. To confirm the CAF-specific role of ADAM17, ADAM17 was also silenced in OSCC cell lines and their migration assessed. Results: OSCC cell-derived C.M. induced upregulation of ADAM17 in NOFs and CAFs. Furthermore, silencing of ADAM17 in NOFs and CAFs downregulated CAF markers and reprogrammed their secretome. C.M. from ADAM17-deficient NOFs or CAFs reduced cancer cell migration and N-cadherin levels. This observation was mirrored by chemically inhibiting N-cadherin in cancer cells. Moreover, ADAM17-deficient CAFs displayed lower levels of the fibroblast growth factor 2 (FGF2), a regulator of cancer cell migration. Chemical targeting of the FGF receptor recapitulated the anti-migratory phenotype of cancer cells and N-cadherin reduction. Conclusions: This project showed that cancer cells upregulate ADAM17 in fibroblasts which, in turn, shed pro-migratory factors, and induce N-cadherin expression in cancer cells. Targeting CAF-associated ADAM17 reversed this phenotype by reducing CAF-derived FGF2. Similarly, inhibiting cancer cell-associated N-cadherin restricted cancer cell migration. Collectively, this study identifies a novel ADAM17-N-cadherin axis contributing to CAF-induced cancer cell migration.