Abstract
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.
Highlights
Head and neck cancer as a whole is heterogeneous
The results showed that TGFB2 (HR = 4.9; 95% CI, 1.4–17; p = 0.015) and TGFBI
By comparative transcriptomic analysis of NOG xenografts derived from oral squamous cell carcinoma (OSCC) cells with high and low epithelial–mesenchymal transition (EMT) scores, the present study identified a four-gene signature consisting of TGFB2, TGFBR2, TGFBI, and FN1, as the cancer-associated fibroblasts (CAFs) index
Summary
Head and neck cancer as a whole is heterogeneous. Gene expression-based clustering methods have established four molecular subgroups of head and neck cancer tissues: basal (BA), mesenchymal (MS), classical (CL), and atypical (AT) [1,2]. In cancers of the breast, lung, and digestive tracts, the mesenchymal subtype is associated with poor prognosis [4,5,6,7]. Tumor cells with the mesenchymal phenotype are thought to derive from undergoing an epithelial–mesenchymal transition (EMT) [8]. EMT is associated with cancer stem cell characteristics, including a more migratory and invasive phenotype that opts for metastasis and drug resistance [6,9]
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