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 11

Spatial mapping reveals a pEMT phenotype in invasive tumor cells.

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Spatial mapping reveals a pEMT phenotype in invasive tumor cells. (A) UM...
(A) UMAP of PTC tumor cell subclustering showing subclusters, pEMT score, and TDS. (B) UMAP labeling PTC subclusters as PTC or pEMT-PTC. (C) Interaction weights between myCAFs and other populations in PTC samples. Left: representative PTC WJL from Luo et al. Line widths depict interaction weights. Right: Box plot depicting interaction weights between myCAFs and PTC or pEMT-PTC in 11 PTC samples containing each population. P value calculated with paired t test. (D) Spatial feature plots of PTC, pEMT-PTC, and myCAF RCTD scores for representative pediatric PTC (Peds08, top), adult PTC (Thy7, middle), and adult mixed PTC/ATC (Thy5, bottom). (E) Spatial cross-correlation analysis between myCAF, PTC, and pEMT-PTC RCTD scores. Top: heatmap showing spatial cross-correlation ordered by hierarchical clustering for representative PTC Peds08. Bottom: box plot showing myCAF spatial cross-correlation with PTC and pEMT-PTC across 12 PTC samples containing PTC and pEMT-PTC cells. P value calculated with paired t test. (F) Representative LAMB3 IHC at the leading edge of PTC. (G) Spatial ligand-receptor interaction weights in PTC. Left: labeling of spatial barcodes by the population with the highest RCTD score in representative PTC Thy7. Right: spatial ligand-receptor interaction weights between labeled populations on the left (line widths indicate interaction weights). Bottom: Box plot showing myCAF interaction weights with PTC and pEMT-PTC across 4 PTCs with sufficient pEMT-PTC spatial barcodes for ligand-receptor interaction analysis. P value calculated with Wilcoxon signed-rank test. (H) Heatmap showing the top 10 signaling patterns in PTC Thy7. Spatial barcode populations at bottom. (I) UMAP of ATC tumor cell subclustering colored by pEMT scores for 2 ATCs with pEMT tumor cell populations. (J) Spatial feature plots of Thy4 with RCTD scores generated by replacing tumor cell clusters with Lu et al. ATC09 subclustering. (K) Box plot showing myCAF spatial cross-correlation with ATC and pEMT-ATC across 7 BRAFV600E ATC samples with pEMT and myCAF populations. P value calculated with paired t test. (L) Representative LAMB3 IHC in BRAFV600E ATC.