Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2020; 11:3687-3687.

Inhibition of fibroblast secreted QSOX1 perturbs extracellular matrix in the tumor microenvironment and decreases tumor growth and metastasis in murine cancer models

Tal Feldman, Iris Grossman-Haham, Yoav Elkis, Patrick Vilela, Neta Moskovits, Iris Barshack, Tomer M. Salame, Deborah Fass _ and Tal Ilani _

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Abstract

Tal Feldman1, Iris Grossman-Haham1, Yoav Elkis2, Patrick Vilela1, Neta Moskovits3, Iris Barshack4, Tomer M. Salame5, Deborah Fass1 and Tal Ilani1

1 Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel

2 Almog Diagnostic, Shoham 6081513, Israel

3 Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel

4 Institute of Pathology, Sheba Medical Center Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel

5 Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel

Correspondence to:

Deborah Fass,email: deborah.fass@weizmann.ac.il
Tal Ilani,email: tal.ilani@weizmann.ac.il

Keywords: monoclonal antibody inhibitor; tumor microenvironment; fibroblasts; extracellular matrix remodeling; disulfide bonds

Received: July 29, 2019     Accepted: December 29, 2019     Published: January 28, 2020

ABSTRACT

Extracellular matrix (ECM) plays an important role in tumor development and dissemination, but few points of therapeutic intervention targeting ECM of the tumor microenvironment have been exploited to date. Recent observations suggest that the enzymatic introduction of disulfide bond cross-links into the ECM may be modulated to affect cancer progression. Specifically, the disulfide bond-forming activity of the enzyme Quiescin sulfhydryl oxidase 1 (QSOX1) is required by fibroblasts to assemble ECM components for adhesion and migration of cancer cells. Based on this finding and the increased QSOX1 expression in the stroma of aggressive breast carcinomas, we developed monoclonal antibody inhibitors with the aim of preventing QSOX1 from participating in pro-metastatic ECM remodeling. Here we show that QSOX1 inhibitory antibodies decreased tumor growth and metastasis in murine cancer models and had added benefits when provided together with chemotherapy. Mechanistically, the inhibitors dampened stromal participation in tumor development, as the tumors of treated animals showed fewer myofibroblasts and poorer ECM organization. Thus, our findings demonstrate that specifically targeting excess stromal QSOX1 secreted in response to tumor-cell signaling provides a means to modulate the tumor microenvironment and may complement other therapeutic approaches in cancer.


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