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Index of Cancer-Associated Fibroblasts Is Superior to the Epithelial–Mesenchymal Transition Score in Prognosis Prediction

1
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan
2
Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 30013, Taiwan
3
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 35053, Taiwan
4
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan
5
PhD Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung City 40227, Taiwan
6
Institute of Information Science, Academia Sinica, Taipei 11529, Taiwan
7
Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung City 40447, Taiwan
8
Department of Otolaryngology, Head and Neck Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
9
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
10
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
11
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(7), 1718; https://doi.org/10.3390/cancers12071718
Received: 3 May 2020 / Revised: 23 June 2020 / Accepted: 25 June 2020 / Published: 28 June 2020
(This article belongs to the Section Tumor Microenvironment)
In many solid tumors, tissue of the mesenchymal subtype is frequently associated with epithelial–mesenchymal transition (EMT), strong stromal infiltration, and poor prognosis. Emerging evidence from tumor ecosystem studies has revealed that the two main components of tumor stroma, namely, infiltrated immune cells and cancer-associated fibroblasts (CAFs), also express certain typical EMT genes and are not distinguishable from intrinsic tumor EMT, where bulk tissue is concerned. Transcriptomic analysis of xenograft tissues provides a unique advantage in dissecting genes of tumor (human) or stroma (murine) origins. By transcriptomic analysis of xenograft tissues, we found that oral squamous cell carcinoma (OSCC) tumor cells with a high EMT score, the computed mesenchymal likelihood based on the expression signature of canonical EMT markers, are associated with elevated stromal contents featured with fibronectin 1 (Fn1) and transforming growth factor-β (Tgfβ) axis gene expression. In conjugation with meta-analysis of these genes in clinical OSCC datasets, we further extracted a four-gene index, comprising FN1, TGFB2, TGFBR2, and TGFBI, as an indicator of CAF abundance. The CAF index is more powerful than the EMT score in predicting survival outcomes, not only for oral cancer but also for the cancer genome atlas (TCGA) pan-cancer cohort comprising 9356 patients from 32 cancer subtypes. Collectively, our results suggest that a further distinction and integration of the EMT score with the CAF index will enhance prognosis prediction, thus paving the way for curative medicine in clinical oncology. View Full-Text
Keywords: cancer-associated fibroblasts; epithelial–mesenchymal transition; oral cancer; tumor stroma; prognosis prediction cancer-associated fibroblasts; epithelial–mesenchymal transition; oral cancer; tumor stroma; prognosis prediction
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Ko, Y.-C.; Lai, T.-Y.; Hsu, S.-C.; Wang, F.-H.; Su, S.-Y.; Chen, Y.-L.; Tsai, M.-L.; Wu, C.-C.; Hsiao, J.-R.; Chang, J.-Y.; Wu, Y.-M.; Robinson, D.R.; Lin, C.-Y.; Lin, S.-F. Index of Cancer-Associated Fibroblasts Is Superior to the Epithelial–Mesenchymal Transition Score in Prognosis Prediction. Cancers 2020, 12, 1718.

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