An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations
Matthew A. Loberg, George J. Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Heather A. Hartmann, Jean-Nicolas Gallant, Courtney J. Phifer, Andres A. Ocampo, Dayle K. Wang, Reilly G. Fankhauser, Kirti A. Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M. Shaddy, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Barbara A. Murphy, Jennifer H. Choe, Jennifer R. Wang, Eric C. Huang, Quanhu Sheng, Luciane T. Kagohara, Elizabeth M. Jaffee, Ryan H. Belcher, Ken S. Lau, Fei Ye, Ethan Lee, Vivian L. Weiss
Matthew A. Loberg, George J. Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Heather A. Hartmann, Jean-Nicolas Gallant, Courtney J. Phifer, Andres A. Ocampo, Dayle K. Wang, Reilly G. Fankhauser, Kirti A. Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M. Shaddy, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Barbara A. Murphy, Jennifer H. Choe, Jennifer R. Wang, Eric C. Huang, Quanhu Sheng, Luciane T. Kagohara, Elizabeth M. Jaffee, Ryan H. Belcher, Ken S. Lau, Fei Ye, Ethan Lee, Vivian L. Weiss
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Research Article Genetics Oncology

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

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.

Authors

Matthew A. Loberg, George J. Xu, Sheau-Chiann Chen, Hua-Chang Chen, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Heather A. Hartmann, Jean-Nicolas Gallant, Courtney J. Phifer, Andres A. Ocampo, Dayle K. Wang, Reilly G. Fankhauser, Kirti A. Karunakaran, Chia-Chin Wu, Maxime Tarabichi, Sophia M. Shaddy, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Barbara A. Murphy, Jennifer H. Choe, Jennifer R. Wang, Eric C. Huang, Quanhu Sheng, Luciane T. Kagohara, Elizabeth M. Jaffee, Ryan H. Belcher, Ken S. Lau, Fei Ye, Ethan Lee, Vivian L. Weiss

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Figure 7

myCAFs are associated with aggressive thyroid cancer tumor phenotypes.

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myCAFs are associated with aggressive thyroid cancer tumor phenotypes. (...
(A) PFS (left) and OS (right) forest plots with IQR hazard ratios and 95% confidence intervals for the VUMC/UW bulk RNA-sequencing cohort split into malignant samples (top) or WDTCs (bottom). Hazard ratios are shown for BRAFV600E mutation and stromal cell ssGSVA scores. (B) PFS (left) and OS (right) survival curves showing the VUMC/UW malignant cohort split into myCAF-high/low by 50th percentile myCAF score. (C) PFS curve of MD Anderson PTC bulk RNA-sequencing cohort split into myCAF-high/low by 50th percentile myCAF score. P values for B and C calculated with log-rank test. (D–H) Box plots depicting primary tumor myCAF score in (D) TCGA PTCs stratified by histology subtype, (E) TCGA PTCs stratified by risk group as defined by the 2009 American Thyroid Association guidelines (43), (F) TCGA PTCs (left) and VUMC/UW malignant cohort (right) stratified by the presence or absence of extrathyroidal extension, (G) TCGA PTCs (left) and VUMC/UW malignant cohort (right) stratified by the presence or absence of lymph node spread, and (H) TCGA PTCs (left) and VUMC/UW malignant cohort (right) stratified by the presence or absence of distant metastasis. (I–L) myCAF score in the VUMC/UW malignant cohort stratified by (I) sample location, (J) presence or absence of indicated high-risk mutations, (K) disease categorization into indolent or aggressive as previously defined (25), and (L) MAP score. P values for D–L calculated with Wilcoxon rank-sum test with Bonferroni correction when more than 2 groups tested.