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

doi:10.1172/JCI169653

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 ZafereoNicholas Navin, Stephen Y. Lai^*, Ruli Gao^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

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.

Original language	English (US)
Article number	e169653
Journal	Journal of Clinical Investigation
Volume	133
Issue number	11
DOIs	https://doi.org/10.1172/JCI169653
State	Published - Jun 1 2023

Funding

We are grateful for the support from Northwestern University (to RG); the Robert H. Lurie Cancer Center (to RG); the Houston Methodist Research Institute (to RG); an MD Anderson Cancer Center CPRIT Single Core seed grant (CPRIT-SC2019, to SYL and RG); the MD Anderson Cancer Center Petrick Multidisciplinary Anaplastic Thyroid Cancer Research Fund (to SYL); an MD Anderson Cancer Center CPRIT Single Core grant (RP180684, to NN); and a Mark Cancer Research Foundation grant (to MZ, RW, and RG). The list of funding institutions is alphabetically ordered by the grant recipient’s last name. We thank Yulong Wang and Weilin Pu for sharing the cell-state annotation data (30) and Heng Xu for sharing the cell-type annotation data (29) that were used in their published work.

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1172/JCI169653

Cite this

Lu, L., Wang, J. R., Henderson, Y. C., Bai, S., Yang, J., Hu, M., Shiau, C. K., Pan, T., Yan, Y., Tran, T. M., Li, J., Kieser, R., Zhao, X., Wang, J., Nurieva, R., Williams, M. D., Cabanillas, M. E., Dadu, R., Busaidy, N. L., ... Gao, R. (2023). Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics. Journal of Clinical Investigation, 133(11), Article e169653. https://doi.org/10.1172/JCI169653

@article{c7097c58328046ebb17d7ede03e22285,

title = "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.",

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

note = "Publisher Copyright: Copyright: {\textcopyright} 2023, Lu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2023",

month = jun,

day = "1",

doi = "10.1172/JCI169653",

language = "English (US)",

volume = "133",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "11",

}

Lu, L, Wang, JR, Henderson, YC, Bai, S, Yang, J, Hu, M, Shiau, CK, Pan, T, Yan, Y, Tran, TM, Li, J, Kieser, R, Zhao, X, Wang, J, Nurieva, R, Williams, MD, Cabanillas, ME, Dadu, R, Busaidy, NL, Zafereo, M, Navin, N, Lai, SY & Gao, R 2023, 'Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics', Journal of Clinical Investigation, vol. 133, no. 11, e169653. https://doi.org/10.1172/JCI169653

TY - JOUR

T1 - Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics

AU - Lu, Lina

AU - Wang, Jennifer Rui

AU - Henderson, Ying C.

AU - Bai, Shanshan

AU - Yang, Jie

AU - Hu, Min

AU - Shiau, Cheng Kai

AU - Pan, Timothy

AU - Yan, Yuanqing

AU - Tran, Tuan M.

AU - Li, Jianzhuo

AU - Kieser, Rachel

AU - Zhao, Xiao

AU - Wang, Jiping

AU - Nurieva, Roza

AU - Williams, Michelle D.

AU - Cabanillas, Maria E.

AU - Dadu, Ramona

AU - Busaidy, Naifa Lamki

AU - Zafereo, Mark

AU - Navin, Nicholas

AU - Lai, Stephen Y.

AU - Gao, Ruli

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85160966247&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85160966247&partnerID=8YFLogxK

U2 - 10.1172/JCI169653

DO - 10.1172/JCI169653

M3 - Article

C2 - 37053016

AN - SCOPUS:85160966247

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 11

M1 - e169653

ER -

Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this