# An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations

## TL;DR

This study maps thyroid cancer progression using single-cell and spatial transcriptomics, identifying fibroblast subtypes linked to aggressive disease.

## Contribution

The study introduces a novel spatial profiling approach to identify prognostic myofibroblast subpopulations in thyroid cancer evolution.

## Key findings

- POSTN+ myofibroblasts correlate with poor prognosis and disease progression in thyroid cancer.
- Inflammatory CAFs are found in autoimmune thyroiditis stromal environments.
- Spatial transcriptomics reveals tumor dynamics in mixed WDTC/ATC tumors.

## Abstract

Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.

Here, we present spatial transcriptomics data highlighting the stromal tumor-dynamics occurring across the spatial evolution of thyroid cancer from indolent to lethal disease.