HrasG12V induces follicular thyroid cancer with attenuated MAPK activation and increased latency compared to KrasG12D

Abstract

RAS mutations are found in nearly 50% of follicular thyroid cancers (FTCs), frequently accompanied by secondary mutations in the P13K/AKT pathway as tumors advance to more poorly differentiated states. To examine the role that oncogenic Hras plays in thyroid tumor initiation and progression, we developed murine models with thyroid-specific expression of HrasG12V combined with heterozygous or homozygous loss of Pten. Loss of Pten cooperated with HrasG12V in a dose-dependent manner to induce the development of follicular thyroid carcinoma and poorly-differentiated thyroid carcinoma. Histopathology of HrasG12V/PtenHom tumors closely resembled those from the established KrasG12D/PtenHom model, but tumor onset was significantly delayed in HrasG12V/PtenHom mice. At three weeks of age, downregulation of MAPK pathway inhibitors was observed in KrasG12D/PtenHom thyroids, accompanied by increased MAPK pathway activation compared to HrasG12V/PtenHom mice. Furthermore, amplification of oncogenic Ras was found in HrasG12V tumors and cell lines, while allelic balance was maintained in KrasG12D models. These studies demonstrate clear phenotypic differences between mutant Hras and Kras in the thyroid and suggest that delayed MAPK activation may mediate the increased tumor latency observed in the HrasG12V/PtenHom model.