Specific functions of the Wnt signaling system in gene regulatory networks throughout the early sea urchin embryo

Wnt signaling affects cell-fate specification processes throughout embryonic development. Here we take advantage of the well-studied gene regulatory networks (GRNs) that control pregastrular sea urchin embryogenesis to reveal the gene regulatory functions of the entire Wnt-signaling system. Five wnt genes, three frizzled genes, two secreted frizzled-related protein 1 genes, and two Dickkopf genes are expressed in dynamic spatial patterns in the pregastrular embryo of Strongylocentrotus purpuratus. We present a comprehensive analysis of these genes in each embryonic domain. Total functions of the Wnt-signaling system in regulatory gene expression throughout the embryo were studied by use of the Porcupine inhibitor C59, which interferes with zygotic Wnt ligand secretion. Morpholino-mediated knockdown of each expressed Wnt ligand demonstrated that individual Wnt ligands are functionally distinct, despite their partially overlapping spatial expression. They target specific embryonic domains and affect particular regulatory genes. The sum of the effects of blocking expression of individual wnt genes is shown to equal C59 effects. Remarkably, zygotic Wnt-signaling inputs are required for only three general aspects of embryonic specification: the broad activation of endodermal GRNs, the regional specification of the immediately adjacent stripe of ectoderm, and the restriction of the apical neurogenic domain. All Wnt signaling in this pregastrular embryo is short range (and/or autocrine). Furthermore, we show that the transcriptional drivers of wnt genes execute important specification functions in the embryonic domains targeted by the ligands, thus connecting the expression and function of wnt genes by encoded cross-regulatory interactions within the specific regional GRNs

Therapeutic strategies for targeting cancer stem cells

The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy; these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies. Compelling evidence suggests that cancer stem cells (CSCs) have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation, relapse, metastasis, and chemo-resistance. Thus, a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates. In this review, the authors characterize and compare different CSC-specific biomarkers that are present in various types of tumors. We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs. This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers, regulating CSC-associated oncogenes and signaling pathways, inhibiting drug-efflux pumps involved in drug resistance, modulating the tumor microenvironment and immune system, and applying drug combination therapy using nanomedicine

Enhancing gene delivery of adeno-associated viruses by cell-permeable peptides

Adeno-associated virus type 2 (AAV2) is considered a promising gene delivery vector and has been extensively applied in several disease models; however, inefficient transduction in various cells and tissues has limited its widespread application in many areas of gene therapy. In this study, we have developed a general, but efficient, strategy to enhance viral transduction, both in vitro and in vivo, by incubating viral particles with cell-permeable peptides (CPPs). We show that CPPs increase internalization of viral particles into cells by facilitating both energy-independent and energy-dependent endocytosis. Moreover, CPPs can significantly enhance the endosomal escape process of viral particles, thus enhancing viral transduction to those cells that have exhibited very low permissiveness to AAV2 infection as a result of impaired intracellular viral processing. We also demonstrated that this approach could be applicable to other AAV serotypes. Thus, the membrane-penetrating ability of CPPs enables us to generate an efficient method for enhanced gene delivery of AAV vectors, potentially facilitating its applicability to human gene therapy

Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment

Only a minority of patients with non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitors. Here the authors design a nanosystem for the co-delivery of a PLK1 inhibitor and PD-L1 antibody, showing anti-tumor immune responses in preclinical lung cancer models