Dll4/Notch1 signalling pathway is required in collective invasion of salivary adenoid cystic carcinoma

High expression of delta-like ligand 4 (Dll4) is reportedly related to the invasion, metastasis, and clinical prognosis of various malignant tumours. Our previous study revealed that collective cell invasion was a common pattern in salivary adenoid cystic carcinoma (SACC). However, the roles of the Dll4/Notch1 signalling pathway in the collective invasion of SACC remain unclear. The present study revealed that Dll4 expression was higher at the invasive front of SACC, and that this upregulation was associated with solid tumour type, high TNM grade, and high rates of metastasis and recurrence. Furthermore, the expression levels of Notch1 and Dll4 were positively correlated at the invasive front, and a three-dimensional (3D) culture model revealed that leader cells showed high expression of Dll4, while follower cells showed high expression of Notch1. Moreover, silencing of Dll4 expression using small interfering RNA reduced the migration, invasion, and collective invasion of SACC cells, and these abilities were rescued by Notch1 overexpression. Finally, SACC collective invasion was increased via the Dll4/Notch1 signalling pathway in experiments that involved a stiff 3D gel, hypoxia and co-culture with human endothelial cells. These findings indicated that the Dll4/Notch1 signalling pathway may be involved in the collective invasion of SACC, which may help to provide possible targets for the treatment of SACC.

Automated summary

High expression of Dll4 is associated with invasive front of SACC, solid tumor type, high TNM grade, and high metastasis and recurrence rates. Notch1 and Dll4 are positively correlated at the invasive front, with leader cells showing high Dll4 expression and follower cells showing high Notch1 expression in a 3D culture model. Silencing Dll4 reduces migration and invasion of SACC cells, but overexpression of Notch1 can rescue these abilities. Dll4/Notch1 signaling pathway may play a role in collective invasion of SACC and could be a potential target for SACC treatment.