A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer

Ion John Campeanu,Manohar Ratnam,C James Block,Guojun Wu,Donovan Watza,Gregory Dyson

doi:10.1038/s41598-019-54282-z

Ion John Campeanu, Manohar Ratnam + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-54282-z

Copy DOI

Abstract

The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. However, these studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. In this study, we comprehensively dissect the associations between multiple EMT transcription factors and EMT markers with stromal and immune tumor infiltration. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. We derive a stroma-corrected ZEB1-activated transcriptional signature and demonstrate that this signature includes several known inhibitors of inflammation, including BMPR2. Finally, multivariate survival analysis reveals that ZEB1 and its expression signature are significantly associated with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content.

Highlights

The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models
As tumor-infiltrating stromal cells express high levels of mesenchymal-associated genes, we examined whether the expression of a set of well-characterized EMT-driving transcription factors was correlated with stromal cell infiltration in multiple cancer types
This study demonstrates that stromal cells within tumors can significantly affect the statistical evaluation of associations between gene expression levels, tumor immune activity, and patient outcomes

Summary

Introduction

The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. These studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. Other studies have attempted to use similar EMT-associated gene signatures to predict survival outcomes in patients[14] These prior inquiries did not account for potential confounding by stromal cell infiltration into the tumor sample[15]. A recent study demonstrated that EMT and stromal cell signatures can confound one another and in general are associated with an altered response to immunotherapy in urothelial carcinoma[16]

Methods

Results

Conclusion