RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination

SIMPLE SUMMARY: RAS mutations occur frequently in thyroid tumors, but the extent to which they are associated to tumor aggressiveness is still uncertain. HRAS proteins occupy different subcellular localizations, from which they regulate distinct biochemical processes. Herein, we demonstrate that the capacity of HRAS-transformed thyroid cells to extravasate and invade distant organs is orchestrated by HRAS subcellular localization, by a mechanism dependent on VEGF-B secretion. Interestingly, aggressiveness inversely correlates with tumor size. Moreover, we have identified the acyl protein thioesterase APT-1, a regulator of HRAS sublocalization, as a determinant of thyroid tumor growth versus dissemination. As such, alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors. In this respect, APT-1 levels could serve as a biomarker that may help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness. ABSTRACT: RAS mutations are the second most common genetic alteration in thyroid tumors. However, the extent to which they are associated with the most aggressive phenotypes is still controversial. Regarding their malignancy, the majority of RAS mutant tumors are classified as undetermined, which complicates their clinical management and can lead to undesired under- or overtreatment. Using the chick embryo spontaneous metastasis model, we herein demonstrate that the aggressiveness of HRAS-transformed thyroid cells, as determined by the ability to extravasate and metastasize at distant organs, is orchestrated by HRAS subcellular localization. Remarkably, aggressiveness inversely correlates with tumor size. In this respect, we also show that RAS site-specific capacity to regulate tumor growth and dissemination is dependent on VEGF-B secretion. Furthermore, we have identified the acyl protein thioesterase APT-1 as a determinant of thyroid tumor growth versus dissemination. We show that alterations in APT-1 expression levels can dramatically affect the behavior of thyroid tumors, based on its role as a regulator of HRAS sublocalization at distinct plasma membrane microdomains. In agreement, APT-1 emerges in thyroid cancer clinical samples as a prognostic factor. As such, APT-1 levels could serve as a biomarker that could help in the stratification of HRAS mutant thyroid tumors based on their aggressiveness.