Lysyl oxidase engineered lipid nanovesicles for the treatment of triple negative breast cancer

Vita, Alessandro De; Liverani, Chiara; Molinaro, Roberto; Martinez, Jonathan O.; Hartman, Kelly A.; Spadazzi, Chiara; Miserocchi, Giacomo; Taraballi, Francesca; Evangelopoulos, Michael; Pieri, Federica; Bongiovanni, Alberto; Mercatali, Laura; Tasciotti, Ennio; Ibrahim, Toni

doi:10.1038/s41598-021-84492-3

Cited by 45 publications

(31 citation statements)

References 50 publications

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“…These investigations could provide more guidance for future potential pre-clinical or clinical studies. Additionally, we will investigate the application of our anti-CD47 mAb for targeted drug delivery via liposomes or other nanoparticles [ 62 , 63 , 64 ] for TNBC treatment.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers

Zhang

Guan

et al. 2021

Vaccines

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Triple-negative breast cancers (TNBCs) are frequently recurrent due to the development of drug resistance post chemotherapy. Both the existing literature and our study found that surface receptor CD47 (cluster of differentiation 47) was upregulated in chemotherapy-treated TNBC cells. The goal of this study was to develop a monoclonal antibody (mAb)-based targeting strategy to treat TNBC after standard treatment. Specifically, a new mAb that targets the extracellular domain of receptor CD47 was developed using hybridoma technology and produced in fed-batch culture. Flow cytometry, confocal microscopy, and in vivo imaging system (IVIS) showed that the anti-CD47 mAb effectively targeted human and mouse TNBC cells and xenograft models with high specificity. The antibody–drug conjugate (ADC) carrying mertansine was constructed and demonstrated higher potency with reduced IC50 in TNBC cells than did the free drug and significantly inhibited tumor growth post gemcitabine treatment in MDA-MB-231 xenograft NSG model. Finally, whole blood analysis indicated that the anti-CD47 mAb had no general immune toxicity, flow cytometry analysis of lymph nodes revealed an increase of CD69+ NK, CD11c+ DC, and CD4+ T cells, and IHC staining showed tumoral infiltration of macrophage in the 4T1 xenograft BALB/cJ model. This study demonstrated that targeting CD47 with ADC has great potential to treat TNBCs as a targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers

Zhang

Guan

et al. 2021

Vaccines

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“…Tumor microenvironment (TME) refers to the surrounding micro-environment where tumor cells exist, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, various signaling molecules, and extracellular matrix (ECM) (44). In various tumors, overexpression of LOX induced by a hypoxic (45). Targeting LOX family-mediated matrix cross-linking as an anti-matrix therapy for solid tumors (46).…”

Section: Discussionmentioning

confidence: 99%

“…Saatci et al demonstrated that targeting LOX can overcome chemotherapy resistance in triple-negative breast cancer ( 4 ). De Vita et al reported: Lysyl oxidase engineered lipid nanovesicles for the treatment of triple-negative breast cancer ( 45 ). Targeting LOX family-mediated matrix cross-linking as an anti-matrix therapy for solid tumors ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of LOX Suggests Poor Prognosis in Gastric Cancer

et al. 2021

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Background: Lysyl oxidase (LOX) is a key enzyme for the cross-linking of collagen and elastin in the extracellular matrix. This study evaluated the prognostic role of LOX in gastric cancer (GC) by analyzing the data of The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset.Methods: The Wilcoxon rank-sum test was used to calculate the expression difference of LOX gene in gastric cancer and normal tissues. Western blot and immunohistochemical staining were used to evaluate the expression level of LOX protein in gastric cancer. Kaplan-Meier analysis was used to calculate the survival difference between the high expression group and the low expression group in gastric cancer. The relationship between statistical clinicopathological characteristics and LOX gene expression was analyzed by Wilcoxon or Kruskal-Wallis test and logistic regression. Univariate and multivariate Cox regression analysis was used to find independent risk factors affecting the prognosis of GC patients. Gene set enrichment analysis (GSEA) was used to screen the possible mechanisms of LOX and GC. The CIBERSORT calculation method was used to evaluate the distribution of tumor-infiltrating immune cell (TIC) abundance.Results: LOX is highly expressed in gastric cancer tissues and is significantly related to poor overall survival. Wilcoxon or Kruskal-Wallis test and Logistic regression analysis showed, LOX overexpression is significantly correlated with T-stage progression in gastric cancer. Multivariate Cox regression analysis on TCGA and GEO data found that LOX (all p < 0.05) is an independent factor for poor GC prognosis. GSEA showed that high LOX expression is related to ECM receptor interaction, cancer, Hedgehog, TGF-beta, JAK-STAT, MAPK, Wnt, and mTOR signaling pathways. The expression level of LOX affects the immune activity of the tumor microenvironment in gastric cancer.Conclusion: High expression of LOX is a potential molecular indicator for poor prognosis of gastric cancer.

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“…With the development of biomaterials, ECM mechanical cues have been shown to participate in proliferation, survival, spread and motility of ECs through mechanotransduction mediated by integrins and the following phosphorylated FAK and paxillin (PXN) [ 15 , [21] , [22] , [23] , [24] ]. ECM stiffens in many pathological processes, including cancer and wound healing [ 25 , 26 ], which remarkably promotes angiogenic outgrowth and branching of ECs [ 27 ]. Moreover, rigid ECM can activate YAP in a Hippo/LATS-cascade-independent manner [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis

Guo

Feng

Huang

et al. 2022

Bioactive Materials

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Endothelial tip cell outgrowth of blood-vessel sprouts marks the initiation of angiogenesis which is critical in physiological and pathophysiological procedures. However, how mechanical characteristics of extracellular matrix (ECM) modulates tip cell formation has been largely neglected. In this study, we found enhanced CD31 expression in the stiffening outer layer of hepatocellular carcinoma than in surrounding soft tissues. Stiffened matrix promoted sprouting from endothelial cell (EC) spheroids and upregulated expressions of tip cell-enriched genes in vitro . Moreover, tip cells showed increased cellular stiffness, more actin cytoskeleton organization and enhanced YAP nuclear transfer than stalk and phalanx ECs. We further uncovered that substrate stiffness regulates FAK and Paxillin phosphorylation in focal adhesion of ECs promoting Rac1 transition from inactive to active state. YAP is subsequently activated and translocated into nucleus, leading to increased tip cell specification. p-Paxillin can also loosen the intercellular connection which also facilitates tip cell specification. Collectively our present study shows that matrix stiffness modulates tip cell formation through p-PXN-Rac1-YAP signaling axis, shedding light on the role of mechanotransduction in tip cell formation. This is of special significance in biomaterial design and treatment of some pathological situations.

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Lysyl oxidase engineered lipid nanovesicles for the treatment of triple negative breast cancer

Cited by 45 publications

References 50 publications

Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers

Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers

Expression of LOX Suggests Poor Prognosis in Gastric Cancer

Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis

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