RAS Subcellular Localization Inversely Regulates Thyroid Tumor Growth and Dissemination.
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2020
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Cancers
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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 a ect 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.
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Thyroid cancer