Ras sublocalization as a regulator of tumour growth and metastasis: an antagonistic tale

Abstract

Primary tumour growth is usually considered to positively correlate with increasing risk of metastatic dissemination. In the case of tumours with low aggressiveness, such as thyroid papillary/follicular tumours, this notion has led to protocols that discard surgery for thyroid nodules with a diameter less than 1cm, based on their, supposedly, low malignancy and low metastatic potential. Here, we demonstrate that thyroid tumour cells harbouring HRAS mutations, display antagonistic proliferative vs metastatic potential depending on HRAS sub-localization: HRAS localized at lipid rafts / Endoplasmic Reticulum generates large primary tumours with low metastatic potential, whereas HRAS presence in disordered membrane / Golgi Complex yields small primary tumours, though highly metastatic. We also demonstrate that altering the expression levels of Acyl Protein Thyoesterase 1 (APT-1), the enzyme responsible for HRAS depalmitoylation, impacts on HRAS sublocalization and, consequently, on tumour behaviour. In the absence of effective RAS inhibitors, APT-1 poses a potential therapeutic target for the treatment of thyroid tumours.