Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development

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 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.

BRAFV600E expression in thyrocytes causes recruitment of immunosuppressive STABILIN-1 macrophages

“…Ryder et al also highlighted the necessity of the CCR2 receptor for macrophage attraction and tumor development using this PTC model [19]. This PTC mouse model indeed presents several advantages: (i) ease of use as it only depends on the presence of two transgenes and the administration of doxycycline [41]; (ii) flexibility in the timing of oncogene induction and in the dose of doxycycline administered (either via food or via intra-peritoneal injections) [21,22]; (iii) short latency and high reproducibility as compared to sporadic thyroid cancer models [42][43][44]; and finally (iv), possibility to study early changes occurring in the thyroid which allows to investigate in situ PTC development as well as the thyroid immune microenvironment, impossible to study in xenograft models in immunosuppressed mice. Indeed, recruitment of TAMs described by Ryder et al in human PTCs is correctly reproduced in this PTC mouse model [45].…”

Role of heterogeneity in dictating tumorigenesis in epithelial tissues

“…Another study in mice thyroid tissue showed that the intrinsic properties of thyroid follicles determined fate of mutant cells. Follicular heterogeneity and thyroid tissue organization dictated the fate of BRAF mutant cells [90], with an increased propensity of BRAF mutants to develop tumor in the postnatal thyroid.…”

Understanding and drugging RAS: 40 years to break the tip of the iceberg

“…This model faithfully recapitulates the tumor histology in RMS patients, and overcomes some caveats from previously developed models of . Lastly, Nilsson and colleagues report a new mouse model of sporadic thyroid carcinoma generated through inducible expression of BRAF V600E ( Schoultz et al, 2021 ). The in vivo RAS-driven cancer models in this issue provide new tools to evaluate therapeutics and to identify new targets for intervention.…”