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 10

Spatial localization of perivascular populations in thyroid cancer.

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Spatial localization of perivascular populations in thyroid cancer. (A–E...
(A–E) Spatial analysis of representative PTC Thy15 showing (A) pathologist annotation of PTC and stromal spatial barcodes, (B) spatial feature plots of PTC and myCAF/pericyte RCTD scores, (C) violin plots of myCAF and pericyte RCTD scores stratified by pathologist annotation, (D) spatial feature plots and violin plots depicting myCAF (POSTN) and pericyte (RGS5) marker gene expression stratified by pathologist annotation, and (E) a heatmap of MERINGUE spatial cross-correlation of myCAF, PTC, and pericyte RCTD scores (ordered by hierarchical clustering). (F) Box plot showing pericyte spatial cross-correlation with myCAF and PTC across 12 PTC samples containing PTC and stromal regions. P value calculated with paired t test. (G) Pathologist annotation of representative PTC regions into predominantly tumor cell or a mix of tumor and fibrovascular cells. Left/middle: zoomed-in hematoxylin and eosin staining (left) with labeled spatial barcodes (middle). Right: zoomed-out hematoxylin and eosin staining with a sample of the spatial barcodes labeled. (H) Violin plots showing PTC and pericyte RCTD scores (left) and pericyte marker RGS5 expression (middle) stratified by pathologist annotation from G. Right: box plots depicting average pericyte RCTD deconvolution scores in PTC or PTC/fibrovascular component mix regions across five samples (Thy15-17, Peds07-08). P value calculated with paired t test. (I) Representative RGS5 IHC of PTC. (J) Pathologist spatial annotation of large perivascular areas (PVAs) (left) and spatial feature plot of vSMC RCTD scores (middle). Right: violin plot of vSMC RCTD score stratified by pathologist large PVA annotation. (K and L) Spatial feature plots (left) and associated violin plots (right) for vSMC marker genes (K) ACTA2 and (L) TAGLN. (M) Box plots showing average vSMC RCTD score (left) or vSMC marker gene expression (right) for 5 tumors stratified by pathologist annotation (Supplemental Figure 10F). P values calculated with paired t test. (N) IHC of αSMA in a representative PTC. Black arrow highlights a large PVA.