Sea Urchin as a Universal Model for Studies of Gene Networks

The purple sea urchin Strongylocentrotus purpuratus has been used for over 150 years as a model organism in developmental biology. Using this model species, scientists have been able to describe, in detail, the mechanisms of cell cycle control and cell adhesion, fertilization, calcium signaling, cell differentiation, and death. Massive parallel sequencing of the sea urchin genome enabled the deciphering of the main components of gene regulatory networks during the activation of embryonic signaling pathways. This knowledge helped to extrapolate aberrations in somatic cells that may lead to diseases, including cancer in humans. Furthermore, since many, if not all, developmental signaling pathways were shown to be controlled by non-coding RNAs (ncRNAs), the sea urchin organism represents an attractive experimental model. In this review, we discuss the main discoveries in the genetics, genomics, and transcriptomics of sea urchins during embryogenesis with the main focus on the role of ncRNAs. This information may be useful for comparative studies between different organisms, and may help identify new regulatory networks controlled by ncRNAs.

HumanaFly: high-throughput transgenesis and expression of breast cancer transcripts in Drosophila eye discovers the RPS12-Wingless signaling axis

Drosophila melanogaster has been a model for multiple human disease conditions, including cancer. Among Drosophila tissues, the eye development is particularly sensitive to perturbations of the embryonic signaling pathways, whose improper activation in humans underlies various forms of cancer. We have launched the HumanaFly project, whereas human genes expressed in breast cancer patients are screened for their ability to aberrate development of the Drosophila eye, hoping to thus identify novel oncogenes. Here we report identification of a breast cancer transgene, which upon expression in Drosophila produces eye malformation similar to the famous Glazed phenotype discovered by Thomas Morgan and decades later dissected to originate from mis-expression of Wingless (Wg). Wg is the ortholog of human Wnt proteins serving as ligands to initiate the developmental/oncogenic Wnt signaling pathway. Through genetic experiments we identified that this transgene interacted with the Wg production machinery, rather than with Wg signal transduction. In Drosophila imaginal discs, we directly show that the transgene promoted long-range diffusion of Wg, affecting expression of the Wg target genes. The transgene emerged to encode RPS12—a protein of the small ribosomal subunit overexpressed in several cancer types and known to also possess extra-ribosomal functions. Our work identifies RPS12 as an unexpected regulator of secretion and activity of Wnts. As Wnt signaling is particularly important in the context of breast cancer initiation and progression, RPS12 might be implicated in tumorigenesis in this and other Wnt-dependent cancers. Continuation of our HumanaFly project may bring further discoveries on oncogenic mechanisms.

Targeting Nodal and Cripto-1: Perspectives Inside Dual Potential Theranostic Cancer Biomarkers

Background:Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents.Objective:To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC).Results:We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate.Conclusion:Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

WNT5A Correlates with Clinicopathological Characteristics in Gastric Cancer: a Meta-Analysis

Background/Aims: Gastric cancer (GC), the third-leading cause of cancer death in the world, is typically diagnosed only in its advanced stages. WNT signaling has been associated with clinicopathological characteristics in diverse cancer types. But the systematic analysis of WNT5A, a member in the signaling, has not been inspected. Thus, our study used a meta-analysis to statistically associate WNT5A expression with GC clinicopathological characteristics. Methods: For a systematic literature review of GC in combination with the WNT signaling molecule WNT5A, we searched for PubMed, Cochrane Library, and Web of Science. It led to the five cohorts, in four eligible studies, consisting of 1,034 patients (617 WNT5A-positive and 417 WNT5A-negative patients). These patients were inspected by the library “meta” in R software for our meta-analysis. Results: Our meta-analysis, revealed a statistically significant associations of WNT5A-positivity with lymph node metastasis (p=0.0047), some types of Lauren diffuse subtype GCs (p<0.0001), advanced tumor depth (p<0.0001), and advanced UICC stages (p=0.0461) with no observation of bias or confounding factors. Conclusions: These results support the feasibility of targeting this embryonic signaling pathway, both for therapy, and as a biomarker to “guide” various individual interventions (i.e., “personalized medicine”).

Decoding the ‘embryonic’ nature of embryonal rhabdomyosarcoma

Embryonal rhabdomyosarcoma is one of the major defined histologic variants of rhabdomyosarcoma that is mainly reported in children. The histologic appearance of this neoplastic entity recapitulates normal myogenesis. The tumor cells variably exhibit the different cellular phases of myogenesis ranging from undifferentiated mesenchymal cells to elongated myoblasts, multinucleated myotubes and differentiated muscle fibers. The carefully orchestrated embryonic signaling pathways that are involved in myogenesis, conceivably also result in the genesis of rhabdomyosarcoma; albeit as a corollary to an imbalance. We have attempted to review the pathogenesis of embryonal rhabdomyosarcoma in an endeavor to understand better, how closely it is linked to normal myogenesis in terms of its molecular dynamics and histologic presentation.