Modeling sporadic thyroid cancer in vivo reveals spatiotemporal control of tumor initiation and clonal growth

We utilized spontaneous Cre-LoxP recombination of BrafCA and a lineage-tracing double-fluorescent reporter allele to uncover, spatiotemporally and at single cell resolution, key features of tumor initiation and tumorigenesis in a conditional mouse thyroid cancer model. The unique histoarchitecture allowed genetic fate mapping of Braf mutant thyroid cells confined to the follicle of origin. Moreover, altered sequence of non-parallel recombination made it possible to distinguish tumor clones that did not activate the reporter due to lost expression of the Cre driver (thyroglobulin promoter). This revealed that papillary thyroid carcinoma, the archetypical Braf-induced thyroid cancer, starts in infancy as follicular neoplasia characterized by oligoclonal growth. Subsequent morphogenesis of multiple papillary tumor subtypes showed both clonal and subclonal traits, different sensitivity to Braf inhibition, increased tumor growth in females, but no uniform coding mutation profile apart from BrafCA.