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

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.

SUBMITTER: Schoultz E

PROVIDER: S-EPMC8380047 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Schoultz Elin E Johansson Ellen E Moccia Carmen C Jakubikova Iva I Ravi Naveen N Liang Shawn S Carlsson Therese T Montelius Mikael M Patyra Konrad K Kero Jukka J Paulsson Kajsa K Fagman Henrik H Bergo Martin O MO Nilsson Mikael M

Disease models & mechanisms 20210811 2

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 follicle ...[more]

PMID: 34379110

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

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

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