The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling

Our plain-English summary of The extracellular matrix protein fibulin-3/EFEMP1 promotes pleural mesothelioma growth by activation of PI3K/Akt signaling, by A. Roshini, C. Goparaju, S. Kundu, et al (Frontiers in Oncology, 2022).

The study

• Authors: A. Roshini, C. Goparaju, S. Kundu, M.S. Nandhu, S.L. Longo, J.A. Longo, J. Chou, F.A. Middleton, H.I. Pass, M.S. Viapiano
• Journal: Frontiers in Oncology
• Published: 2022;12:1014749
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

Copyright © 2022 Roshini, Goparaju, Kundu, Nandhu, Longo, Longo, Chou, Middleton, Pass and Viapiano.

In plain English

This laboratory study examined whether fibulin-3, a protein found at high levels in the pleural fluid of people with malignant pleural mesothelioma, helps these tumors grow. The authors used human tissue samples, mesothelioma and normal cell lines, public cancer gene data (TCGA), and mice with human mesothelioma cells implanted in the chest. Asbestos exposure was not studied. Among 36 tumor types in the gene data, mesothelioma had the highest fibulin-3 expression. Lowering fibulin-3 in mesothelioma cells reduced their viability, colony formation, migration and invasion. It also increased the cells' sensitivity to cisplatin, at concentrations the authors noted were higher than those used clinically. Raising fibulin-3 in normal mesothelial cells increased their viability, colony formation, motility and invasion. Fibulin-3 activated PI3K/Akt signaling. In one mesothelioma cell line, a PI3K inhibitor blocked fibulin-3's increase of PI3K-dependent gene expression and of viability. In mice, two weeks of an experimental anti-fibulin-3 antibody (mAb428.2) reduced tumor signal and extended survival in both models. In one model, 30% of treated animals had reduced or stable disease at 15 weeks. The authors concluded that fibulin-3 is not only a prognostic factor but also a relevant molecular target in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on human mesothelioma and normal mesothelial cell lines, analysis of human tissue and public gene-expression data, and treatment experiments in mice implanted with human mesothelioma cells
• Who was studied: MPM tumors and normal mesothelial tissues from the NYU Early Detection Research Network laboratory (number not given). Human cell lines including normal mesothelial LP-9 and MPM lines H226, MSTO211H, H2595, H2596, H2452, H2373, H2461, HP1 and HP3. TCGA mesothelioma dataset (N=87). 8-week-old athymic nude mice (10 or more per arm for survival, 5 per arm for histology).
• Exposure: No asbestos or other fiber exposure was studied. The experimental variables were raising or lowering fibulin-3 levels in cells, the PI3K inhibitor LY294002, cisplatin, and an anti-fibulin-3 chimeric antibody (mAb428.2, 30 mg/kg per day by injection into the pleural space for two weeks) compared with control human IgG.
• Main results:
  • In TCGA gene-expression data from 36 types of solid and liquid tumors, malignant mesothelioma had the highest absolute expression of fibulin-3.
  • In MPM cell lines HP1 and H2595, fibulin-3 knockdown reduced cell viability and colony formation. Overexpression in normal LP-9 mesothelial cells increased viability and colony formation.
  • In H2595 cells, combining fibulin-3 knockdown with cisplatin further decreased viability. The cisplatin concentrations used were higher than those applicable clinically.
  • Fibulin-3 knockdown reduced migration and invasion of HP1 and H2595 cells, and reduced invasion of H2596 cells. Overexpression in LP-9 cells increased motility and invasion.
  • Fibulin-3 activated PI3K/Akt signaling. In H2596 cells, the PI3K inhibitor LY294002 abolished fibulin-3's increase of PI3K-dependent gene expression and of cell viability.
  • In mice with implanted H2595 or H226 tumors, mAb428.2 reduced tumor luminescence and significantly extended survival in both models. In the H2595 model, 30% of animals had reduced or stable disease at 15 weeks.
  • In H226 tumors from mice euthanized one week after treatment (N=5 mice per treatment), mAb428.2 significantly reduced the proliferation marker Ki67.
• The authors' conclusion: The authors concluded that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors.
• Limitations the authors state:
  • The cisplatin concentrations used were higher than those applicable in a clinical setting.
  • Survival experiments were ended at 15 weeks because the tumors grow slowly and their spread in the chest was hard to assess.
  • The overall mechanism, including the identity of fibulin-3 receptors on MPM cells, was not fully worked out.
  • Fibulin-3 may activate additional pathways in mesothelioma cells that this study did not reveal.
  • TCGA data did not show a correlation of fibulin-3 expression with tumor stage or grade.

Topics

Medical terms in this study, explained in our Lexicon: Fibulin-3, Pleural Mesothelioma, Prognosis, Pleural Effusion, Biomarker, Mesothelial Cells.

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