Although most papillary thyroid cancers (PTCs) are deemed to have a favorable clinical course and outcome, some develop an aggressive biological behavior at diagnosis or during treatment. Single-cell RNA sequencing (scRNA-seq), which is based on quantifying the features of individual cells to resolve tumor tissue heterogeneity, was used to uncover gene regulatory relationships and trace the transcriptional trajectories underlying the malignant transformation. In this study, we performed single-cell sequencing on samples from four PTC patients and one benign thyroid tumor patient. These included two papillary thyroid microcarcinoma cancers (PTMC) patients, two age-matched advanced PTC patients with invading surrounding tissues, and one patient undergoing surgical treatment due to a benign thyroid tumor. We constructed a new PTC RNA spectrum using single-cell sequencing. Single-cell sequencing analysis indicated that there was a highly invasive subgroup in the PTC epithelial cells, the expression of SATB2 (special AT-rich binding protein-2) was related to the prognosis and clinical progress of PTC, and SATB2 could promote the proliferation, migration, and invasion of PTC cells. We found that NOTCH1 was the key target gene of SATB2, and the activation of the SATB2/NOTCH1 pathway was one of the reasons for the high carcinogenicity of this subgroup.