A group of scientists led by Associate Professor of Medicine Andreas Herrlich, Division of Nephrology, has used a functional genomics approach to identify key signaling pathways as novel regulators of transforming growth factor-alpha (TGFα) shedding in cancer cells. The article is published in the January 2018 issue of Molecular Cancer Research. (MCR)
Ectodomain shedding (or, release) of cell-surface precursor proteins by metalloproteinases produces cellular signaling molecules important in disease. Activation of the epidermal growth factor receptor (EGFR) by shed ligand TGFα is linked to cancer development, growth and metastasis, and resistance to cancer therapeutics. The release of TGFα is mainly carried out by ADAM17, a member of the A-disintigrin and metalloprotease (ADAM) domain family.
It is important to target EGFR ligand shedding to successfully inhibit the EGFR pathway. Excessive shedding of EGFR ligands such as TGFα can “outcompete” therapeutic inhibition of EGFR. Targeting, or drugging, the metalloproteases directly to regulate ectodomain shedding fails clinically because it indiscriminately affects the shedding of numerous ligands.
First author Jennifer L. Wilson, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, and co-workers used a combined experimental and computational network approach to identify novel regulators of induced TGFα cleavage.
The group first performed an shRNA screen for signaling regulators of TGFα shedding, using a library of 750 kinases and phosphatases in Jurkat cells, an acute T cell leukemia-derived cell line. After identifying a cohort of genes that affect TGFα ectodomain release, they vetted the selections computationally and then validated positive and negative regulators of TGFα cleavage in several cancer cell types.
They found an unexpected connection between regulators of the NfκB pathway and the release by ectodomain cleavage of cancer growth factors of the EGFR ligand family.
“In our study we used genomic screens and network analysis to define drug targets in signaling pathways that regulate epidermal growth factor release,” says Dr. Herrlich. “Because the signaling circuitry in cells is similar, our results suggest not only new treatment opportunities for EGFR-driven cancers but also for EGFR-driven chronic kidney disease, the main focus of our studies in the lab.”
Many of the identified genes were not predicted oncogenes by traditional expression, mutation, or activation methods, highlighting the benefit of their strategy of selecting therapeutic targets based on a functional role.
Eirini Kefaloyianni, Instructor of Medicine, WU Nephrology.
Read the full article Functional Genomics Approach Identifies Novel Signaling Regulators of TGFα Ectodomain Shedding here. Authors: Jennifer L. Wilson, Eirini Kefaloyianni, Lauren Stopfer, Christina Harrison, Venkata S. Sabbisetti, Ernest Fraenkel, Douglas A. Lauffenburger and Andreas Herrlich.
The article is acknowledged in the Highlights of This Issue section of the January issue of MCR.