Vertaisarvioitu alkuperäisartikkeli tai data-artikkeli tieteellisessä aikakauslehdessä (A1)

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development




Julkaisun tekijät: Schoultz E, Johansson E, Moccia C, Jakubikova I, Ravi N, Liang S, Carlsson T, Montelius M, Patyra K, Kero J, Paulsson K, Fagman H, Bergo MO, Nilsson M

Kustantaja: COMPANY BIOLOGISTS LTD

Julkaisuvuosi: 2022

Journal: Disease Models and Mechanisms

Tietokannassa oleva lehden nimi: DISEASE MODELS & MECHANISMS

Lehden akronyymi: DIS MODEL MECH

Volyymi: 15

Sivujen määrä: 16

ISSN: 1754-8403

eISSN: 1754-8411

DOI: http://dx.doi.org/10.1242/dmm.048887

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

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


Tiivistelmä
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.

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Last updated on 2022-22-04 at 14:57