Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development



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

Publisher: COMPANY BIOLOGISTS LTD

: 2022

: Disease Models and Mechanisms

: DISEASE MODELS & MECHANISMS

: DIS MODEL MECH

:  dmm048887

: 15

: 16

: 1754-8403

: 1754-8411

DOI: https://doi.org/10.1242/dmm.048887

: https://journals.biologists.com/dmm/article/15/2/dmm048887/271800/Tissue-architecture-delineates-field-cancerization

: https://research.utu.fi/converis/portal/detail/Publication/174565418


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.

Last updated on 2024-26-11 at 17:58