Systemic Delivery of Tumor-Targeting siRNA Nanoparticles against an Oncogenic LncRNA Facilitates Effective Triple-Negative Breast Cancer Therapy

Vaidya, Amita; Sun, Zhanhu; Ayat, Nadia; Schilb, Andrew; Liu, Xujie; Jiang, Hongfa; Sun, Da; Scheidt, Josef; Qian, Victoria; He, Siyuan; Gilmore, Hannah; Schiemann, William P.; Lü, Zheng Rong

doi:10.1021/acs.bioconjchem.9b00028

Cited by 129 publications

(113 citation statements)

References 60 publications

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“…Vaidya et al describe an effective TNBC therapy that uses nanoparticle-mediated transfer of RNAi molecules targeting the TNBC/CSC enriched lncRNA DANCR [132]. This therapy led to reduced tumor progression and was associated with no side effects in a murine xenograft model of TNBC.…”

Section: Therapeutic Targetsmentioning

confidence: 99%

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

Brown

Wasson

Marcato

2020

Cells

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Treatment decisions for breast cancer are based on staging and hormone receptor expression and include chemotherapies and endocrine therapy. While effective in many cases, some breast cancers are resistant to therapy, metastasize and recur, leading to eventual death. Higher percentages of tumor-initiating cancer stem cells (CSCs) may contribute to the increased aggressiveness, chemoresistance, and worse outcomes among breast cancer. This may be particularly true in triple-negative breast cancers (TNBCs) which have higher percentages of CSCs and are associated with worse outcomes. In recent years, increasing numbers of long non-coding RNAs (lncRNAs) have been identified as playing an important role in breast cancer progression and some of these have been specifically associated within the CSC populations of breast cancers. LncRNAs are non-protein-coding transcripts greater than 200 nucleotides which can have critical functions in gene expression regulation. The preclinical evidence regarding lncRNA antagonists for the treatment of cancer is promising and therefore, presents a potential novel approach for treating breast cancer and targeting therapy-resistant CSCs within these tumors. Herein, we summarize the lncRNAs that have been identified as functionally relevant in breast CSCs. Furthermore, our review of the literature and analysis of patient datasets has revealed that many of these breast CSC-associated lncRNAs are also enriched in TNBC. Together, this suggests that these lncRNAs may be playing a particularly important role in TNBC. Thus, certain breast cancer-promoting/CSC-associated lncRNAs could be targeted in the treatment of TNBCs and the CSCs within these tumors should be susceptible to anti-lncRNA therapy.

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Section: Therapeutic Targetsmentioning

confidence: 99%

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

Brown

Wasson

Marcato

2020

Cells

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“…Total cellular protein was extracted as previously described (Vaidya et al, 2019). Protein extracts (40 µg) were run on SDS-PAGE, transferred onto nitrocellulose membrane and immunoblotted with primary antibodies overnight.…”

Section: Methodsmentioning

confidence: 99%

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

Vaidya

Wang

Qian

et al. 2019

Preprint

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invasiveness 28 Abbreviations 29 BCa -Breast cancer 30 EDB-FN -Extradomain-B fibronectin 31 FN1 -Fibronectin 32 MRI -Magnetic resonance imaging 33 PET -Positron-emission tomography 34 CT -Computed tomography 35 TME -Tumor microenvironment 36 ECM -Extracellular matrix 37 TGF-β -Transforming growth factor-β 38 EMT -Epithelial to mesenchymal transition 39 CEA -Carcinoembryonic antigen 40 41 42 43 44 45 46 47 48 49 50 51 Summary Statement 52 Dynamic changes in invasive properties of breast cancer cells directly influence extradomain-B 53 fibronectin levels, suggesting its potential role as a molecular marker for active surveillance and 54 therapeutic monitoring of breast cancer. 55 Abstract 56Breast tumor heterogeneity is a major impediment to oncotherapy. Tumor cells undergo rapid 57 clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of 58 specific markers of these high-risk tumors precludes efficient therapeutic and diagnostic 59 management of breast cancer. Given the critical function of tumor microenvironment in the 60 oncogenic circuitry, we sought to determine the role of the extracellular matrix oncoprotein, 61 extradomain-B fibronectin (EDB-FN), as a molecular marker of aggressive cancers. High-risk 62 invasive cell lines generated from relatively less invasive MCF7 and MDA-MB-468 breast cancer 63 cells by long-term TGF-β treatment and chemoresistance demonstrated hybrid epithelial-64 mesenchymal phenotype, enhanced motility, and significantly elevated EDB-FN levels in 2D-and 65 3D-cultures. To determine if EDB-FN could serve as a therapy-predictive marker, the invasive cell 66 lines were treated with MK2206-HCl, a pan-AKT inhibitor. Phospho-AKT depletion reduced 67 EMT and invasion of the populations, with a concomitant decrease in EDB-FN expression, partly 68 through the phosphoAKT-SRp55 pathway, demonstrating that EDB-FN expression is strongly 69 associated with high-risk breast cancer. EDB-FN is a promising molecular marker for accurate 70 detection, differential diagnosis, and non-invasive therapeutic surveillance of aggressive breast 71 cancer. 72 73 74 75 76 77 78 79Breast cancer (BCa) is a devastating disease that accounts for 41,000 deaths each year in 80 the US (Siegel et al., 2018). Although the survival rate for patients with localized BCa is close to 81 99%, it declines precipitously in patients with distant metastases and drug resistance (Siegel et al., 82 2018, DeSantis et al., 2017). A major stumbling block in the clinical management of the disease 83 is tumor heterogeneity, which plays a role in the dynamic nature of BCa progression (Baird and 84 Caldas, 2013). Whole genome sequencing and profiling studies have demonstrated that breast 85 tumors of the same histological subtype exhibit distinct molecular portraits and discrete trajectories 86 in individual BCa patients at different stages (Tsang and Tse, 2019, Eliyatkin et al., 2015, Baird 87 and Caldas, 2013). Stochastic mutations, genome instability, and clonal evolution arising from 88 selective pre...

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“…ECO/siRNA nanoparticles have been shown to mediate effective RNAi of various oncogenic targets in vitro and in vivo [8‐10]. To further confirm the role of eIF4E in PCa cells, the effects of down‐regulation of eIF4E were assessed using RNAi based on ECO/siRNA nanoparticles.…”

Section: Figurementioning

confidence: 99%

“…The precise role of eIF4E in EMT, invasion, and chemoresistance in PCa is still to be established with consideration of different subpopulations in order to develop precision medicine for PCa. In this work, we aimed to explore the role of eIF4E in EMT, invasion, and chemoresistance in PCa for establishing a promising new therapeutic strategy by regulating eIF4E expression using (1-aminoethyl)iminobis[Noleicylcysteinyl-1-aminoethyl) propionamide] (ECO)/small interfering RNA (siRNA) nanoparticles previously developed in our lab [8][9][10] for PCa therapy in the context of tumor heterogeneity.Two PCa cell lines (PC3 and DU145) and their corresponding paclitaxel (PTX)-resistant cell lines (PC3-DR and DU145-DR) were investigated to assess the role of eIF4E Abbreviations: ECO, (1-aminFoethyl)iminobis[N-oleicylcysteinyl-1-aminoethyl) propionamide]; eIF4E, eukaryotic translation initiation factor 4E; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; MMP3, matrix metalloproteinase 3; PCa, prostate cancer; PTX, paclitaxel; siRNA, small interfering RNA.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.…”

mentioning

confidence: 99%

“…The expression of eIF4E followed the same trend with the expression of mesenchymal markers in all four cell lines, regardless of drug resistance. Considering the results of morphology, EMT, and invasiveness of all four cell lines, it was found that eIF4E ECO/siRNA nanoparticles have been shown to mediate effective RNAi of various oncogenic targets in vitro and in vivo [8][9][10]. To further confirm the role of eIF4E in PCa cells, the effects of down-regulation of eIF4E were assessed using RNAi based on ECO/siRNA nanoparticles.…”

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confidence: 99%

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Role of eIF4E on epithelial‐mesenchymal transition, invasion, and chemoresistance of prostate cancer cells

Liu

Vaidya

Sun

et al. 2020

Cancer Communications

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Systemic Delivery of Tumor-Targeting siRNA Nanoparticles against an Oncogenic LncRNA Facilitates Effective Triple-Negative Breast Cancer Therapy

Cited by 129 publications

References 60 publications

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

Role of eIF4E on epithelial‐mesenchymal transition, invasion, and chemoresistance of prostate cancer cells

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