Syntaxin-1a, a synaptic-related protein in breast and head and neck cancer progression and prognosis

Resumen

Modern oncology conceives solid tumours as organs by themselves, meaning that not only should the behaviour of cancer cells to be considered and evaluated therapeutically, but also the so-called tumour microenvironment. Even though much research has been done on the influence of several cellular and molecular components of the microenvironment on tumour progression, only a few studies have focused on the direct influence of neurons and tumour innervation in promoting tumour growth and metastasis, or the role of neural-related proteins, expressed in cancer cells, on the different cancer hallmarks. In the context of this second line of research, our group published in 2016 an article demonstrating the differential expression of neurogenes in breast cancer (BC) subtypes and their correlation with patient overall survival. Among them, Syntaxin-1A (STX1A), a synaptic-related protein and a member of the SNARE family of proteins, was found overexpressed in HER2-positive (HER2-enriched and luminal B) in comparison to the HER2-negative (luminal A and basal) BC subtypes. This project is focused on BC but also studies STX1A in head and neck squamous cell carcinoma (HNSCC), considering that the BC is the first cancer-related death in women and that the incidence of HNSCC is expected to increase by 30% in 2030. Understanding the role of STX1A in the tumour biology of BC and HNSCC may lead to proposing this neurogene as a prognostic biomarker and as a targetable candidate to treat these cancers. Particularly, the expression of STX1A and other SNARE-family members has been investigated in BC and HNSCC patient databases, as well as whether STX1A could be involved in cell proliferation, treatment sensitivity and invasion and metastasis processes in BC and HNSCC. On one hand, STX1A has been found overexpressed in BC and HNSCC tumours in comparison to healthy tissues, and high expression of this neurogene correlates with a poorer overall survival of BC and HNSCC patients and with a shorter metastasis-free period in BC. On the other hand, STX1A supresses cell proliferation by enhancing G2/M checkpoint and decreasing Cyclin D1 expression in vitro. Also, STX1A expression restrains BC and HNSCC tumour growth in vivo, in comparison to tumours with impaired STX1A function. Moreover, a functional link between STX1A and the EGFR/HER family of receptors is described. EGF induces STX1A clustering and STX1A is involved in EGFR and HER2 plasma membrane turnover and signal transduction. Also, in HER2-positive BC and HNSCC, STX1A modulates sensitivity to lapatinib, an anti-HER2 targeted therapy, likely due to the differential expression of EGFR and HER2 at the plasma membrane. Non-functional STX1A cells become more sensitive to lapatinib in vitro and in vivo. Finally, STX1A promotes invasion and metastasis by facilitating cell adhesion and spreading in BC and HNSCC cells in vitro. In conclusion this novel research work has unveiled the role of STX1A in BC and HNSCC cancer progression and prognosis, positioning STX1A as a putative survival biomarker and as a promising therapeutic target to sensitize to lapatinib treatment and to supress invasion and metastasis events in BC and HNSCC tumours.