Department of Biochemistry and Molecular Genetics, and.
Center for Cancer Genomics, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois, USA.
J Clin Invest. 2023 Jun 1;133(11):e169653. doi: 10.1172/JCI169653.
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.
最致命的间变性甲状腺癌（ATC）通常由惰性分化型甲状腺癌（DTC）转化而来；然而，肿瘤内复杂的转化过程仍知之甚少。我们通过使用来自不同甲状腺癌亚型患者的单细胞转录组学和遗传改变数据，对间变性转化模型进行了剖析，包括细胞谱系和细胞命运转变。由此产生的 ATC 转化谱包括应激反应性 DTC 细胞、炎症性 ATC 细胞（iATC）、有丝分裂缺陷性 ATC 细胞，并一直延伸到间充质 ATC 细胞（mATC）。此外，我们的分析确定了 2 个重要的里程碑：（a）二倍体阶段，其中 iATC 细胞是具有炎症表型的二倍体细胞；（b）非整倍体阶段，其中 mATC 获得非整倍体基因组和间充质表型，产生大量胶原和胶原相互作用受体。与此同时，癌相关成纤维细胞表现出间充质细胞类型之间的强烈相互作用，巨噬细胞从 M1 状态转变为 M2 状态，T 细胞从细胞毒性状态转变为耗竭状态，这为 ATC 的治疗提供了新的治疗机会。
