Tissue architecture delineates field cancerization in brafv600e-induced tumor development

Elin Schoultz, Ellen Johansson, Carmen Moccia, Iva Jakubikova, Naveen Ravi, Shawn Liang, Therese Carlsson, Mikael Montelius, Konrad Patyra, Jukka Kero, Kajsa Paulsson, Henrik Fagman, Martin O. Bergo, Mikael Nilsson

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review


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 BRAFmutant 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.

TidskriftDMM Disease Models and Mechanisms
StatusPublished - 2022 feb.

Ämnesklassifikation (UKÄ)

  • Cancer och onkologi


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