Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures

Faiz M Khan,Susanne Knoll,Julio Vera,David Engelmann,Ulf Schmitz,Shailendra K Gupta,Alf Spitschak,Brigitte M Pützer,Olaf Wolkenhauer,Stephan Marquardt

doi:10.1038/s41467-017-00268-2

Abstract

Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial–mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.

Highlights

Cancer is a disease of subverted regulatory pathways
Our studies revealed that vascular endothelial growth factor-C (VEGF-C) and its cognate receptor VEGFR-3, both highly upregulated in cancer cells with abundant E2F1 expression, are direct targets of this transcription factor[21]
By mapping gene expression profiles from cancer cell lines displaying the features of epithelial–mesenchymal transition (EMT) transition onto the E2F1 interaction map, we identify a tumor type-specific regulatory core

Summary

Introduction

Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. Correspondence and requests for materials should be addressed to Recent advances in sequencing and omics technologies provide us with data that can be used to identify and characterize cancer and tumor-specific molecular networks The analyses of these networks have given insights into various aspects of carcinogenesis, tumor progression, and metastasis[1, 2]. The set of mutated, deregulated, or epigenetically modified cancer genes is highly patient and tumor-type variable, and more important, these genes are integrated in a small set of regulatory pathways[2]. These pathways are not isolated: they crosstalk to shape and fine-tune basic cellular phenotypes that are subverted in cancer. In the context of solid tumors, unbalanced E2F1 regulation can lead to the emergence of aggressive tumor cells, which drive cancer progression, resistance to anti-cancer drugs, and the rise of metastatic lesions[9,10,11,12,13]

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Conclusion