Abstract
ABSTRACT: Differentiated thyroid cancer primarily classified by tumor histology comprises follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC), which represent distinct malignancies regarding the pattern of tumor spreading, responsiveness to radioiodine treatment, and clinical outcome. As FTC and PTC also differ genetically i.e., RAS mutations predominate in FTC whereas mutant BRAF is much more frequent in PTC, it is assumed although yet unproven that the archetypical tumor growth pattern – follicular versus papillary – depends on mutation identity and potentially the graded signaling output of the MAPK pathway that differs in response to constitutive activation by RAS or BRAF. In this study, we show by clonal tracing in mice carrying a Braf mutant allele with targeted expression of BRAFV600E exclusively in the thyroid gland that sporadically developed tumors either adopt a follicular or a papillary phenotype depending on follicle origin. Moreover, a single tumor clone may transit from papillary to follicular growth associated with asymmetric distribution of stromal tissue in the immediate vicinity of the tumor. Key to these observations is monitoring the progeny of cells undergoing spontaneous recombination of both BrafCA and the reporter gene because of Cre leakage which, in contrast to after induced oncogene activation comprising all target cells, implies that tumors develop stochastically and asynchronously originating from a limited number of BRAF mutant cells and taking place within a preserved thyroid tissue microenvironment. The results suggest that the natural heterogeneity of follicles and tumor cell plasticity modify BRAFV600E-induced neoplastic growth leading to divergent tumor histogenesis. SIGNIFICANCE: Cell-of-origin intrinsic features rather than driver mutation identity influence tumor growth patterning in differentiated thyroid cancer and might impact histopathologic diagnosis of thyroid carcinoma subtypes.