Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics
Lina Lu, Jennifer Rui Wang, Ying C. Henderson, Shanshan Bai, Jie Yang, Min Hu, Cheng-Kai Shiau, Timothy Pan, Yuanqing Yan, Tuan M. Tran, Jianzhuo Li, Rachel Kieser, Xiao Zhao, Jiping Wang, Roza Nurieva, Michelle D. Williams, Maria E. Cabanillas, Ramona Dadu, Naifa Lamki Busaidy, Mark Zafereo, Nicholas Navin, Stephen Y. Lai, Ruli Gao
Lina Lu, Jennifer Rui Wang, Ying C. Henderson, Shanshan Bai, Jie Yang, Min Hu, Cheng-Kai Shiau, Timothy Pan, Yuanqing Yan, Tuan M. Tran, Jianzhuo Li, Rachel Kieser, Xiao Zhao, Jiping Wang, Roza Nurieva, Michelle D. Williams, Maria E. Cabanillas, Ramona Dadu, Naifa Lamki Busaidy, Mark Zafereo, Nicholas Navin, Stephen Y. Lai, Ruli Gao
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Research Article Genetics Oncology

Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics

Abstract

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.

Authors

Lina Lu, Jennifer Rui Wang, Ying C. Henderson, Shanshan Bai, Jie Yang, Min Hu, Cheng-Kai Shiau, Timothy Pan, Yuanqing Yan, Tuan M. Tran, Jianzhuo Li, Rachel Kieser, Xiao Zhao, Jiping Wang, Roza Nurieva, Michelle D. Williams, Maria E. Cabanillas, Ramona Dadu, Naifa Lamki Busaidy, Mark Zafereo, Nicholas Navin, Stephen Y. Lai, Ruli Gao

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Figure 4

Activation of iATC and mATC signatures in thyroid cancer.

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Activation of iATC and mATC signatures in thyroid cancer. (A and C) Dot ...
(A and C) Dot plots depict the predicted cell subtype compositions. Normal, PTC, and PTC states are combinations of all cells in each sample type. ATC plots are for individual patients. Data in A are from Luo et al. (29), and data in C are from Pu et al. (30). (B and D) Heatmaps showing scaled expression levels of the 59-gene signature with detection in 2 published data sets. (E) Coclustering of TCGA bulk RNA-Seq data from Nishant et al. (23), with in-house pseudobulk analysis of scRNA-Seq data based on a union of TFC and tumor-specific genes (Supplemental Table 3). (F) Kaplan-Meier plot of overall survival of DTC patients with partial activation of ATC and PTC phenotypes. P values were determined by 2-sided log-rank test. +, censored observations.