Long non-coding RNAs (lncRs), by virtue of their versatility and multilevel gene regulation, have emerged as attractive pharmacological targets for treating heterogenous and complex malignancies like triple-negative breast cancer (TNBC). Despite multiple studies on lncRNA functions in tumor pathology, systemic targeting of these "undruggable" macromolecules with conventional approaches remains a challenge. Here, we demonstrate effective TNBC therapy by nanoparticlemediated RNAi of the oncogenic lncRNA DANCR, which is significantly overexpressed in TNBC. Tumor-targeting RGD-PEG-ECO/siDANCR nanoparticles were formulated via selfassembly of multifunctional amino lipid ECO, cyclic RGD peptide-PEG, and siDANCR for systemic delivery. MDA-MB-231 and BT549 cells treated with the therapeutic RGD-PEG-ECO/ siDANCR nanoparticles exhibited 80-90% knockdown in the expression of DANCR for up to 7 days, indicating efficient intracellular siRNA delivery and sustained target silencing. The RGD-PEG-ECO/siDANCR nanoparticles mediated excellent in vitro therapeutic efficacy, reflected by the significant reduction in the invasion, migration, survival, tumor spheroid formation, and proliferation of the TNBC cell lines. At the molecular level, functional ablation of DANCR

Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the expression profile of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN) in invasive breast cancer. Analyses of TCGA/GTEx databases and immunostaining of clinical samples found a significant overexpression of EDB-FN in breast tumors, which correlated with poor overall survival. Significant upregulation of EDB-FN was observed in invasive cell populations generated from relatively less invasive MCF7 and MDA-MB-468 cells by long-term TGF-β treatment and acquired chemoresistance. Treatment of the invasive cell populations with an AKT inhibitor (MK2206-HCl) reduced their invasive potential, with a concomitant decrease in their EDB-FN expression, partly through the phosphoAKT-SRp55 pathway. EDB-FN downregulation, with direct RNAi of EDB-FN or indirectly through RNAi of SRp55, also resulted in reduced motility of the invasive cell populations, validating the correlation between EDB-FN expression and invasion of breast cancer cells. These data establish EDB-FN as a promising molecular marker for non-invasive therapeutic surveillance of aggressive breast cancer.

Surgical sutures are vulnerable to bacterial infections and biofilm formation. At the suture site, pain and undesirable, excess inflammation are additionally detrimental to wound healing. The development of a polymerized cyclodextrin (pCD) coated surgical suture introduces the capability to locally deliver both anti‐inflammatory and anti‐microbial drugs throughout the phases of acute and chronic healing. Local delivery allows for the improvement of wound healing while reducing related systemic side effects and drug resistance. Through testing, it has been shown that the fabrication of our pCD coating minimally affects the suture's mechanical properties. In vitro studies show measurable and consistent drug delivery for nearly 5 weeks. The therapeutic level of this delivery is sufficient to show inhibition of bacterial growth for 4 weeks, and free‐radical scavenging (an in vitro anti‐inflammatory activity approximation) for 2 weeks. With this pCD coating technique, we maintain clinical performance standards while also introducing a long‐term dual delivery system relevant to the wound healing timeframe. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.

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...

Breast cancer often metastasizes to bone and causes osteolytic lesions. Dynamic changes in the bone microenvironment are rarely studied but are hypothesized to influence the establishment and progression of bone metastatic lesions. Here, we developed an experimental bone metastasis mouse model to detect and characterize breast cancer cell homing and the onset of early bone metastasis. We studied the dissemination of cancer cells to (intact) bones, their proliferative state and direct microenvironment, using 3D light-sheet fluorescence microscopy (LSFM) and multiscale correlative tissue characterization. We show that cancer cells home in all bone compartments using intact bones, with a preference for small clusters in the bone marrow and larger clusters in the periosteum. We developed an image analysis tool to detect and track early bone osteolytic lesions, quantifying their onset, location and growth. Osteolytic lesions were only detected in the metaphysis and were classified as three different types depending on location. Surprisingly, we observed altered bone (re)modeling with increased new bone formation in animals without detectable osteolytic lesions. Our study suggests an early systemic effect of breast cancer cells in the bone microenvironment and provides novel insights of the structural and biophysical changes during the early phase of metastasis.