Introduction and expression of PIK3CA E545K in a papillary thyroid cancer BRAF V600E cell line leads to a dedifferentiated aggressive phenotype

Abstract

Abstract Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CA E545K into the LAM1 PTC cell line, which carries a BRAF V600E mutation. In culture, the engineered cell line (LAM1:PIK3CA E545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CA E545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of disease progression. While tumour weights and volumes were not significantly higher in LAM1:PIK3CA E545K mice, there was a decrease in expression of thyroid differentiation markers TTF-1, thyroglobulin, PAX8 and B-catenin, suggesting that introduction of PIK3CA E545K led to dedifferentiation in vivo. Collectively, this study provides evidence of a role for PIK3CA E545K in driving disease progression from a well-differentiated to an undifferentiated thyroid cancer; however, over-expression was not a determinant of an accelerated growth phenotype in ATC. Graphical Abstract

Keywords

• Papillary thyroid cancer
• Anaplastic thyroid cancer
• Disease progression
• Dedifferentiation