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  • Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development.

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development.

Disease models & mechanisms (2021-08-12)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Millipore
MILLIPLEX® Mouse Pituitary Magnetic Bead Panel - Endocrine Multiplex Assay, The analytes available for this multiplex kit are: ACTH, BDNF, FSH, GH, Prolactin, TSH, LH.
Sigma-Aldrich
Anti-BRAF (V600E) antibody, Rabbit monoclonal, recombinant, expressed in HEK 293 cells, clone RM8, purified immunoglobulin