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Antibody-drug conjugate αEGFR-E-P125A reduces triple-negative breast cancer vasculogenic mimicry, motility, and metastasis through inhibition of EGFR, integrin, and FAK/STAT3 signaling

ABSTRACT: Primary tumor growth and metastasis in triple-negative breast cancer (TNBC) require supporting vasculature, which develop through a combination of endothelial angiogenesis and vasculogenic mimicry (VM), a process associated with aggressive metastatic behavior in which vascular-like structures are lined by tumor cells. We developed αEGFR-E-P125A, an antibody-endostatin fusion protein that delivers a dimeric, mutant endostatin (E-P125A) payload that inhibits TNBC angiogenesis and VM in vitro and in vivo. To characterize the mechanisms associated with induction and inhibition of VM, RNA-seq of MDA-MB-231-4175 TNBC cells grown in a monolayer (2D) was compared to cells plated on Matrigel undergoing VM (3D). We then compared RNA-seq between TNBC cells in 3D and cells in 3D with VM inhibited by αEGFR-E-P125A (αEGFR-E-P125A). Gene set enrichment analysis (GSEA) demonstrated that VM induction activated the IL6-JAK-STAT3 and angiogenesis pathways, which were downregulated by αEGFR-E-P125A treatment. Correlative analysis of the phospho-proteome demonstrated decreased EGFR phosphorylation at Y1069, along with decreased phosphorylation of focal adhesion kinase (FAK) Y397 and STAT3 Y705 sites downstream of α5β1 integrin. Suppression of phosphorylation events downstream of EGFR and α5β1 integrin demonstrated that αEGFR-E-P125A interferes with ligand-receptor activation, inhibits VM, and overcomes oncogenic signaling associated with EGFR and α5β1 integrin crosstalk. In vivo, αEGFR-E-P125A treatment decreased primary tumor growth and VM, reduced lung metastasis, and confirmed the inhibition of signaling events observed in vitro. Simultaneous inhibition of EGFR and α5β1 integrin signaling by αEGFR-E-P125A is a promising strategy for the inhibition of VM, tumor growth, motility, and metastasis in TNBC and other EGFR-overexpressing tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253789 | GEO | 2024/01/29

REPOSITORIES: GEO

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Project description:Breast cancer is the first type of cancer in term of incidence in the world with only 36% of survival at 5 years. This poor prognosis is mainly due to metastasis formation. Cell migration is a key process in nature and the understanding of its complex mechanisms has a crucial importance in biomaterials, engineering, medicine, cell biology and immunology. Cells can detect chemical and physical gradients both on surface and in solution and respond to them with oriented movement. Therefore, controlling such processes could potentially result in major advances in biochemistry and biotechnology with potential breakthroughs in metastasis treatment and tissue regeneration. After a thorough investigation on current literature, but also basing our foundations on our previous results published by Marega et al, Small (2016), this research project focusses on the integrins α5β1 and αvβ3, already known to be implicated in cell migration, angiogenesis and resistance to cell death. Such transmembrane receptors can be activated indirectly by EGFR pathway or directly by IGD type I fibronectin motifs. The influence of both integrin invalidation will be studied on cell migration in usual culture plates and on IGDQ-exposing surfaces. In this work known as PACMAN (Peptide-Assisted Cellular Migration Along eNgineered surfaces) project, we have recently shown in an in vitro model migration that IGDQ-exposing (IsoLeu-Gly-Asp-Glutamine type I Fibronectin motif) monolayers (SAMs) on gold sustain the migration of MDA-MB-231 cells by triggering Focal Adhesion Kinase. In this project, such tunable scaffolds are used to mimic the extracellular environment, being able to induce and control cell migration on an anisotropic surface. The observed migratory behavior induced by the IGDQ-bearing peptide gradient along the surface suggests the presence of cell subpopulations associated with a “stationary” or a “migratory” phenotype, the latter determining a considerable cell migration at the sub-cm length scale. Those subpopulations with a “stationary” or a “migratory” phenotype obtained was characterized by a single-cell RNA-sequencing in order to identify new pathways regulating the metastasis process. The aim of this work is to highlight the pathways implied into the integrin-dependent cell migration and to find putative therapeutic, diagnostic or prognostic targets. That will permit a better molecular stratification of tumors and will improve the therapeutic personalization.

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Antibody-drug conjugate αEGFR-E-P125A reduces triple-negative breast cancer vasculogenic mimicry, motility, and metastasis through inhibition of EGFR, integrin, and FAK/STAT3 signaling

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