Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF-mutant lineage becomes a cancerized lineage. The TgCreERT2;BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.

Department of Biosciences and Nutrition Karolinska Institute Huddinge SE 14183 Sweden

Department of Clinical Pathology Sahlgrenska University Hospital Göteborg SE 41345 Sweden

Department of Endocrinology University of Turku Åbo FI 20521 Finland

Department of Radiology Institute of Clinical Sciences University of Gothenburg SE 41345 Göteborg Sweden

Division of Clinical Genetics Department of Laboratory Medicine Lund University Lund SE 22184 Sweden

Faculty of Medicine Charles University Hradec Kralove Czech Republic

Sahlgrenska Center for Cancer Research Department of Medical Chemistry and Cell Biology Institute of Biomedicine University of Gothenburg SE 40530 Göteborg Sweden

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