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 BRAFV600E from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky CRE activity 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 type. 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 sporadic thyroid cancer model provides a new tool to evaluate drug therapy at different stages of tumor evolution.
Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development
Present address: EMBL Barcelona, Career del Dr. Aiguader 88, Barcelona, Spain.
Present address: Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Present address: Faculty of Medicine, Charles University, Hradec Kralove, Czech Republic.
These authors contributed equally to this work
Currently Viewing Accepted Manuscript - Newer Version Available
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; Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development. Dis Model Mech 2021; dmm.048887. doi: https://doi.org/10.1242/dmm.048887
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