Neuropilin 2 role in the regulation of disseminated tumour cells dormancy ans metastasis in breast and head and neck cancer

Resumen

Metastases are considered the last stage of tumour progression and the main cause of death associated to solid tumours. There are no effective treatments for metastasis which remain non-curable with more than 90% of patients dying from metastatic disease. They derive from disseminated tumour cells (DTCs) that can remain occult in a dormant state while adapting to the new microenvironment. By mechanisms that are still unclear, dormant DTCs can re-activate and become proliferative giving rise to metastatic outgrowth. Therefore, understanding the mechanisms by which metastases are formed is essential to face one of the most important problems in clinical oncology. Metastasis development depends on DTCs survival in circulation as well as on their ability to colonize new microenvironments. Therefore, we propose that the tumour microenvironment regulates the fate and survival of DTCs in secondary organs, hence regulating metastases. This project has been developed in order to decipher the role of the nervous system in breast cancer (BrCa) and head and neck cancer (HNSCC) progression and metastasis. Particularly, we have investigated whether the neurogene neuropilin 2 (NRP2) has a crucial role in regulating DTCs biology and in remodelling the metastatic niche generating a favourable microenvironment for the survival and proliferation of the DTCs, all stimulating metastasis. As classical partners of NRPs, we have also studied the effect of class 3 semaphorins (SEMA3s) and their receptors, plexins (PLXNs), on tumour cells biology. On one hand, we have shown that SEMA3F has an anti-tumour effect in vivo increasing quiescence markers expression and inducing a switch in primary tumours behaviour to a more dormant phenotype. We have also shown that it diminishes cell dissemination to secondary organs, which makes SEMA3F a potential good prognosis factor in BrCa and HNSCC. On the other hand, our results suggest that PLXNA2 inhibits tumour growth as well as prevents cell migration and invasion while it might modulate cell stemness. Moreover, we have also found that PLXNA3 might restrain tumour growth in oestrogen receptor (ER)-positive breast tumours and that the oestrogen signalling up-regulates PLXNA3 expression, associating PLXNA3 with longer dormancy periods of ER-positive breast tumours. Finally, we have mainly focused on deciphering the role of NRP2 in regulating DTCs biology and lung metastases. Here, we have shown that NRP2 positively regulates BrCa and HNSCC cells proliferation, adhesion, migration, invasion and survival in vitro and in vivo. NRP2 deletion clearly inhibits tumour growth in vivo as well as decreases the number and size of lung metastases. Moreover, NRP2 is essential for lung DTCs proliferative phenotype, hence promoting lung metastases growth in vivo. Highlighting the role of the microenvironment, we have shown that the lung microenvironment up-regulates NRP2 expression partly by macrophages and fibroblasts-derived TGFβ1. Altogether, this thesis contributes to a better understanding of DTCs biology describing TGFβ1-NRP2 axis as a dormancy inhibitor pathway, promoting DTCs re-awakening and lung metastases development. The negative correlation of NRP2 expression with metastasis free survival in BrCa and HNSCC patients’ and our results emphasizing the metastatic role of NRP2, suggest that NRP2 could be a bad prognosis biomarker and a good target to design new drugs against metastasis.