Supplementary data from: Single-cell analysis identifies ATC-like cells driving progression in relapsed follicular thyroid carcinoma

Follicular thyroid carcinoma (FTC) is prone to early distant metastasis
and has a poor prognosis compared with papillary thyroid carcinoma (PTC).
This study aimed to unravel the cellular and molecular mechanisms
underlying FTC progression and its transformation into the aggressive
anaplastic thyroid carcinoma (ATC). Through single-cell RNA sequencing
(scRNA-seq) profiling of 46,739 cells from PTC, follicular variant PTC
(FVPTC), relapsed FTC (RFTC), and ATC, we reconstructed a comprehensive
molecular trajectory of thyroid carcinoma progression. Our analysis
revealed that PTC, FVPTC, and FTC possess distinct yet converging pathways
of dedifferentiating into ATC, with FVPTC also progressing to FTC. In
RFTC, we identified a unique cluster of cells exhibiting ATC molecular
characteristics. These cells interact with endothelial cells and
fibroblasts mainly via the COL9A3-integrin α1β1 complex, and may exhibit
high metabolic and proliferative potential. UBE2C was identified as a
specific marker for this population, which we termed “ATC-like cells.”
Functional validation in vitro and in vivo confirmed that UBE2C was
markedly upregulated in FTC and was associated with adverse clinical
outcomes. Mechanistically, UBE2C promoted cell proliferation and tumor
growth, and regulated D-arginine and D-ornithine metabolism, glutathione
metabolism, glycerophospholipid metabolism and tryptophan metabolism in
FTC. This reveals a previously unrecognized population of ATC-like cells
in RFTC marked by high UBE2C expression. UBE2C contributes to FTC
progression by enhancing proliferation and modulating key metabolic
pathways, suggesting it as both a critical biomarker of aggressive disease
and a potential therapeutic target.