Endocrine Abstracts

JOINT664

Background: Thyroid cancer (TC) progression involves distinct mutation-specific pathways, primarily driven by BRAF and RAS mutations. These mutations influence epithelial cell states and tumor microenvironment (TME) dynamics, but their differential effects remain largely unexplored.

Methods: We conducted a multimodal genomic and transcriptomic analysis, integrating single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing across BRAF-driven (PTC-B, ATC-B) and RAS-driven (FTC-R, ATC-R) TCs. Additional validation was performed using public datasets.

Results: In ATCs, the proportion of epithelial cells decreased, while TME components expanded, as confirmed by multimodal transcriptomic analysis. Pseudotime analysis revealed distinct dedifferentiation pathways, with BRAF-driven TCs undergoing gradual dedifferentiation and RAS-driven TCs showing abrupt epithelial transitions, suggesting mutation-specific pathogenesis. Intracellular pathway activation also varied, with ATC-B exhibiting antigen processing/presentation and B-cell receptor signaling activation, while ATC-R displayed upregulation of EMT, hypoxia, and ECM-related pathways. TME-epithelial interactions, particularly those involving fibroblasts, were significantly increased in ATC-R, aligning with pseudotime trajectory shifts. Furthermore, receptor-ligand interactions differed between DTCs and ATCs, with those localized in stroma or ATC regions strongly correlating with poorer survival outcomes, emphasizing the role of mutation-driven TME remodeling.

Conclusions: Epithelial distribution, dedifferentiation trajectories, and TME interactions differ significantly between BRAF- and RAS-driven TCs, suggesting mutation-specific pathogenesis. These findings highlight the importance of considering epithelial states and mutation profiles when selecting TME-targeted therapeutic strategies, emphasizing the potential for personalized diagnosis and treatment.