Thyroid cancer organoid models: dissecting carcinogenesis and developing target therapies

Organoid systems have emerged as a powerful alternative to bridge the gap between traditional 2D cell lines and animal models in cancer research. While both models have been instrumental in studying cancer, they often fall short in capturing the early molecular mechanisms driving carcinogenesis. To overcome these limitations, our lab is focused on generating in vitro models of thyroid cancer using pluripotent stem cells.

Understanding the initial events that lead to cancer initiation and progression is crucial for improving thyroid cancer diagnosis and therapy. However, the absence of a genetically tractable model has significantly limited our knowledge of the molecular drivers of thyroid cancer. Notably, no studies to date have utilized an in vitro embryonic stem cell-derived model to investigate the initiation of thyroid cancer.

Our lab has successfully generated functional thyroid tissue in a three-dimensional culture system derived from both mouse and human embryonic stem cells. Using this platform, we demonstrated that overexpression of the BrafV637E mutation in functional mESC-derived thyroid follicles leads to the formation of PTC-like organoids, which was shown to be a valuable model for drug screening studies.

Current Research Goals

We are now expanding our efforts by using human thyroid organoids not only to generate cancer models but also to explore the mechanisms underlying human thyroid carcinogenesis. Our approach involves genetically engineered human ESCs with a tamoxifen-inducible system to conditionally express key thyroid oncogenes, including: BRAFV600E – Modeling Papillary Thyroid Carcinoma (PTC), RASQ61R – Modeling Follicular Thyroid Carcinoma (FTC) and BRAFV600E + TP53 knockdown – Modeling Anaplastic Thyroid Carcinoma (ATC)

These in vitro thyroid cancer models will allow us to investigate:

1. The impact of thyroid oncogene activation at different stages of thyroid development

2. Early molecular events involved in thyroid cancer initiation

3. The role of p53 in thyroid cancer progression

4. Mechanisms contributing to drug resistance

By leveraging stem cell-derived organoid technology and gene editing tools, our research aims to provide unprecedented insights into thyroid cancer biology, paving the way for novel diagnostic strategies and targeted therapies.