Single cell and spatial transcriptome profiling identifies KLF6 as a EMT driver in metastatic PTC

Distant metastasis (DM) is a major prognostic determinant in papillary thyroid carcinoma (PTC), with the 10-year overall survival rate remaining below 20% among patients with radioiodine-refractory DM. To investigate the role of EMT in thyroid cancer metastasis, single-cell RNA sequencing (scRNA-seq) data from nine PTC samples without distant metastasis (non-DM) and five PTC samples with DM were analyzed. Here we show, a distinct subset of S100A2+ malignant EPCs in the DM group underwent EMT-mediated trans-differentiation into POSTN+ CAFs, which subsequently differentiated into THY1+ CAFs. These findings were supported by spatial transcriptomics and pseudotemporal trajectory analysis. Intercellular communication analysis further identified KLF6 as a key transcriptional regulator of EMT, and its elevated expression was associated with poor prognosis in PTC with DM. In vitro and in vivo experiments confirmed that KLF6 promotes PTC proliferation, invasion, EMT, and DM. Collectively, KLF6-activated TGF-β signaling induces EMT of S100A2+ malignant EPCs into POSTN+ CAFs and THY1+ CAFs, thereby facilitating DM in PTC. Single-cell RNA sequencing and spatial transcriptomics data from nonmetastatic and distant metastatic papillary thyroid carcinomas are analysed to reveal epithelial-mesenchymal transition mechanisms.