Single-cell RNA Sequencing Reveals the Heterogeneity in Differentiation Trajectory and Tumor Microenvironment Leading to More Aggressive Phenotypes of Papillary Thyroid Cancer in Children and Young Adult Patients

The tumor ecosystem heterogeneity of papillary thyroid carcinoma (PTC) is poorly characterized especially in children and young adult patients (CAYA-PTC). Here, we used single-cell RNA sequencing to profile transcriptomes map from eleven patients’ paratumors and localized tumors, covering comprehensive clinical courses of PTC. Compared with adult-PTC, CD4T_Tfh and CD8T_Tex cells were significantly higher in CAYA-PTC patients which closely related to metastasis. Along the differentiation trajectory, we discover three phenotypes of thyrocytes population (normal, BRAF-like, Fusion-like), whose composition shapes bulk molecular subtypes and tumor characteristics. Furthermore, our data identifies CAYA-PTC patients lack a “mild-state (BRAF-like)” malignant thyrocyte population. This different differentiation states indicates PTC cells quickly develop into invasion and metastasis in CAYA patients, while they gradually progress over a long time in adult patients. In addition, extracellular matrix cancer-associated fibroblasts(emCAFs_LAMP5) interact with endothelial cells and thyrocytes, ultimately promoting tumor angiogenesis and metastasis, which plays a more evident role in CAYA patients. FAP was highly expressed in emCAF_LAMP5 and positive correlated with LAMP5 in CAYA-PTC tissues. Therefore, ⁶⁸Ga-FAPI-PET have the potential to be used as a promising diagnostic method for CAYA patients with failed by traditional 18F-FDG-PET/CT. Together, our findings provide insight into the CAYA-PTC ecosystem that suggests distinct diagnostic, prognostic and therapeutic implications compared to adults.