Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding
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Author(s)
Kefaloyianni, Eirini
Harrison, Christina
Sabbisetti, Venkata S.
Herrlich, Andreas
Wilson, Jennifer Lynn
Stopfer, Lauren Elizabeth
Fraenkel, Ernest
Lauffenburger, Douglas A
Date Issued
October 2017
Journal
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Citation
Wilson, Jennifer L. et al. “Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding.” Molecular Cancer Research 16, 1 (October 2017): 147–161 © 2017 American Association for Cancer Research
Version
Author's final manuscript
Abstract
Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signalingmolecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFκB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFκB regulatory functions. Inflammatory regulators thus also govern cancer cell growth-promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer. Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1158/1541-7786.MCR-17-0140
