Mutation-specific dynamics of dedifferentiation trajectories and tumor-stromal interactions in thyroid cancer

Progression from differentiated thyroid cancer to anaplastic thyroid cancer (ATC) involves profound epithelial plasticity and remodeling of the tumor microenvironment (TME), but how BRAF^V600E and RAS driver mutations shape these processes remains unclear. Here, we integrated single-nucleus RNA-seq, spatial transcriptomics, and bulk RNA-seq across BRAF^V600E- and RAS-driven thyroid tumors to delineate mutation-specific progression trajectories. BRAF^V600E-driven tumors exhibited a gradual dedifferentiation trajectory with immune pathway activation, whereas RAS-driven tumors displayed abrupt transitions characterized by aneuploidy, epithelial-mesenchymal transition, hypoxia, and extracellular matrix remodeling. Cancer-associated fibroblasts (CAFs) emerged as key regulators, with mutation-specific ligand-receptor interactions: integrin-based signaling predominated in BRAF^V600E-mutant ATCs, while PLAU-PLAUR, TNFSF10-TNFRSF10B, and AREG-EGFR were additionally enriched in RAS-driven ATCs. These CAF-epithelial circuits were spatially validated and associated with poor prognosis. Together, our findings reveal mutation-dependent epithelial and TME dynamics associated with thyroid cancer dedifferentiation and highlight the potential importance of molecular-tailored approaches in the management of advanced thyroid cancer.