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Tissue architecture delineates field cancerization in brafv600e-induced tumor development

Schoultz, Elin ; Johansson, Ellen ; Moccia, Carmen ; Jakubikova, Iva ; Ravi, Naveen LU ; Liang, Shawn ; Carlsson, Therese ; Montelius, Mikael ; Patyra, Konrad and Kero, Jukka LU , et al. (2022) In DMM Disease Models and Mechanisms 15(2).
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.... (More)

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 BRAFmutant 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Braf mutation, Cancer, Development, Oligoclonal, Oncogenic activation, Thyroid
in
DMM Disease Models and Mechanisms
volume
15
issue
2
article number
dmm048887
publisher
The Company of Biologists Ltd
external identifiers
  • scopus:85113846120
  • pmid:34085700
ISSN
1754-8403
DOI
10.1242/DMM.048887
language
English
LU publication?
yes
id
c33e58fe-4754-495e-bd2c-f07471007765
date added to LUP
2021-09-17 08:40:37
date last changed
2024-04-20 11:18:59
@article{c33e58fe-4754-495e-bd2c-f07471007765,
  abstract     = {{<p>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 BRAFmutant 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.</p>}},
  author       = {{Schoultz, Elin and Johansson, Ellen and Moccia, Carmen and Jakubikova, Iva and Ravi, Naveen and Liang, Shawn and Carlsson, Therese and Montelius, Mikael and Patyra, Konrad and Kero, Jukka and Paulsson, Kajsa and Fagman, Henrik and Bergo, Martin O. and Nilsson, Mikael}},
  issn         = {{1754-8403}},
  keywords     = {{Braf mutation; Cancer; Development; Oligoclonal; Oncogenic activation; Thyroid}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{The Company of Biologists Ltd}},
  series       = {{DMM Disease Models and Mechanisms}},
  title        = {{Tissue architecture delineates field cancerization in brafv600e-induced tumor development}},
  url          = {{http://dx.doi.org/10.1242/DMM.048887}},
  doi          = {{10.1242/DMM.048887}},
  volume       = {{15}},
  year         = {{2022}},
}