Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21st century cancer therapeutics

Yi-Hong Zhou1, Yuanjie Hu1, Liping Yu2, Chao Ke3, Christopher Vo1, Hao Hsu1, Zhenzhi Li1, Anne T. Di Donato1, Abhishek Chaturbedi1, Ji Won Hwang1, Eric R. Siegel4, Mark E. Linskey1

1Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA

2Real-Time PCR, Ziren Research LLC, Irvine, CA, USA

3Neurosurgery, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

4Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Correspondence to:

Yi-Hong Zhou, email: yihongz@uci.edu

Keywords: EFEMP1, EGFR, NOTCH1, MMP2, cell invasion, glioma, tumor cell subpopulation, orthotopic tumors, tumor vascularization

Received: January 14, 2016     Accepted: May 13, 2016     Published: July 08, 2016


De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cell-context-dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment.

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