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Schoultz E, Johansson E, Moccia C, et al. Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development. Dis Model Mech. 2021;15(2)doi: 10.1242/dmm.048887.
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, M. O., & Nilsson, M. (2022). Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development. Disease models & mechanisms, 15(2), . https://doi.org/10.1242/dmm.048887
Schoultz, Elin, et al. "Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development." Disease models & mechanisms vol. 15,2 (2022). doi: https://doi.org/10.1242/dmm.048887
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. Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development. Dis Model Mech. 2022 Feb 01;15(2). doi: 10.1242/dmm.048887. Epub 2021 Aug 11. PMID: 34379110; PMCID: PMC8380047.
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Dis Model Mech. 2022 Feb 01;15(2). doi: 10.1242/dmm.048887. Epub 2021 Aug 11.

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

Disease models & mechanisms

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

Affiliations

  1. Sahlgrenska Center for Cancer Research, Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-40530 Göteborg, Sweden.
  2. Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic.
  3. Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund SE-22184, Sweden.
  4. Department of Radiology, Institute of Clinical Sciences, University of Gothenburg, SE-41345 Göteborg, Sweden.
  5. Department of Endocrinology, University of Turku, Åbo FI-20521, Finland.
  6. Department of Clinical Pathology, Sahlgrenska University Hospital, Göteborg SE-41345, Sweden.
  7. Department of Biosciences and Nutrition, Karolinska Institute, Huddinge SE-14183, Sweden.

PMID: 34379110 PMCID: PMC8380047 DOI: 10.1242/dmm.048887

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.

© 2021. Published by The Company of Biologists Ltd.

Keywords: Braf mutation; Cancer; Development; Oligoclonal; Oncogenic activation; Thyroid

Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

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