Invasion and metastasis of cancer cells, as well as their resistance to treatment, are the major causes of patient death. Clear cell renal cell carcinomas (ccRCCs) account for B70% of kidney cancers; and metastasis occurs in about 30–40% of these patients.

Most ccRCCs originate from the lining epithelium of the renal tubules in the kidney, which face peripheral body fluids. Acquisition of mesenchymal properties by cancer cells, even transiently, via processes resembling epithelial– mesenchymal transition is thought to be a critical event for the development of malignancy and metastasis into distant areas.

This may occur through the enhancement of the resistance to anoikis to maintain cell survival rates during their distant metastasis or possibly also through facilitating the motility and invasive activities of cancer cells. Moreover, the acquisition of mesenchymal properties is often coupled with the resistance of cancer cells to therapeutic drugs.

Arf6, which is a small GTPase primarily regulating the recycling of plasma membrane components, and its downstream effector AMAP1 (also called ASAP1 and DDEF1) are frequently overexpressed in breast cancers, and constitute a signalling pathway that promotes invasion and metastasis of cancer cells by downregulating E-cadherin-based cell–cell adhesion and upregulating recycling of b1 integrins.

Clinically, robust expression of Arf6 pathway components in primary breast tumours statistically correlates with tumour malignancy and the poor overall survival of patients. The Arf6 pathway appears to also exist in subpopulations of lung adenocarcinomas and head and neck cancers, and statistically correlates with their metastatic recurrence and poor outcomes.

ccRCCs and breast cancers both originate mainly from cells located within epithelial ductal structures. Moreover, for both of them acquisition of mesenchymal properties are thought to be critical for malignant development. Researchers investigated whether ccRCCs also utilize the Arf6-based pathway for their malignancy development, including their drug resistance.

The results demonstrate that ccRCCs also frequently overexpress components of the Arf6-based mesenchymal pathway, and that this pathway is activated by G-protein-coupled receptors (GPCRs) rather than RTKs in ccRCCs. The Arf6-based mesenchymal pathway not only promotes invasion and metastasis, but crucially contributes to drug resistance.

The results identify the molecular machinery that drives the mesenchymal-type malignancy of large populations of primary ccRCCs, which is critical to the poor overall survival of patients.