Abstract 93: Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression

Abstract Anaplastic thyroid cancer (ATC) is arguably the most lethal human malignancy, with a median survival of ~12 weeks. About half of ATC tumors arise from within differentiated forms of thyroid cancer types, most commonly papillary thyroid cancer (PTC), suggesting an evolutionary continuum from PTC to ATC. In contrast to the extreme lethality of ATC, PTC are typically indolent with long life-histories. The molecular mechanisms driving ATC progression from PTC have been challenging to resolve, mostly due to the heterogenous cellular populations that are undergoing dynamic changes during ATC progression. In this study, we applied high throughput 3'-scRNAseq in an unbiased analysis of cell populations in thyroid tumors. We analyzed 90,990 single cell transcriptomes from 8 ATC tumors, 8 PTC tumors and 5 normal thyroids. To make the precise inference of tumor cell lineages, we stratified the epithelial cells into 5 categories by calculating genotypes from scRNAseq data that include: (1) normal epithelial cells in normal thyroids, (2) PTC epithelial cells in PTC tumors, (3) PTC tumor cells in PTC tumors, (4) ATC epithelial cells in ATC tumors, (5) ATC tumor cells in ATC tumors. We then constructed the full epithelial cell development trajectories from normal epithelial to PTC and ATC tumor cells. Our results show that co-existing epithelial and mesenchymal phenotypes is a major characteristic of ATC tumor cells and epithelial-mesenchymal transition (EMT) drives ATC developmental trajectory. We further analyzed the transcriptional programs of immune cell types and their interactions with tumor cells. Our data suggested a unique sub-population of helper T cell and a distinct B cell subtype arise in the tumor microenvironment in response to ATC progression. Collectively, our results identify EMT as the major driving force of thyroid cancer aggressiveness and provide novel insights regarding the immunological remodeling in response to ATC progression. Citation Format: Xi Chen, Jennifer Rui Wang, Ying Henderson, Yuanqing Yan, Shanshan Bai, Rachel Kieser, Min Hu, Jiping Wang, Nicholas Navin, Stephen Lai, Ruli Gao. Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 93.