title: Weaponizing human EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) for 21stcentury cancer therapeutics.
abstract: De-regulatedEFEMP1gene 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 ofEFEMP1were 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 ofin vitroassays 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 cellcontext- 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.
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Zhou
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Real-Time PCR, Ziren Research LLC, Irvine, CA, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Neurosurgery, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ke
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Vo
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Hsu
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Zhenzhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Di Donato
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chaturbedi
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Hwang
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Siegel
authors.affiliation: Neurosurgery, Brain Tumor Research Laboratory, University of California Irvine, Irvine, CA, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Linskey
keywords: EFEMP1; EGFR; MMP2; NOTCH1; cell invasion; glioma; orthotopic tumors; tumor cell subpopulation; tumor vascularization