Format

Send to

Choose Destination
Mol Cancer Res. 2018 Jan;16(1):147-161. doi: 10.1158/1541-7786.MCR-17-0140. Epub 2017 Oct 10.

Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding.

Author information

1
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
2
Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri.
3
Department of Biology, University of Massachusetts, Boston, Massachusetts.
4
Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.
5
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
6
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts. aherrlich@wustl.edu lauffen@mit.edu.
7
Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri. aherrlich@wustl.edu lauffen@mit.edu.

Abstract

Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. 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. Mol Cancer Res; 16(1); 147-61. ©2017 AACR.

PMID:
29018056
PMCID:
PMC5859574
[Available on 2019-01-01]
DOI:
10.1158/1541-7786.MCR-17-0140

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center