Targeting ERβ to fight melanoma: a new valid approach?

The impact of sex steroids and their cognate receptors in many human cancers has been almost neglected for many years. Gender disparities in melanoma, with a female advantage in its incidence and outcome have been reported. However, the molecular aspects of these findings remain still pending, with few reports so far collected on the role of estrogen receptors (ERs), alpha (ERα) or beta (ERβ), or G-protein coupled estrogen receptor (GPER) in this cancer. ERs both mediate estrogen signaling through genomic or non-genomic mechanism, which might cooperate each other to regulate a range of responses in target tissues and human cancers. The subsequent discovery that an orphan GPCR (GPR30, then renamed GPER) is required for rapid estrogen signaling opened new perspectives in estrogen biology and hormone-dependent cancers [3]. ERβ can be detected in benign nevi, pre-malignant and malignant melanocytic lesions. As such, it might represent a hallmark of melanoma progression. A role for GPER has been also proposed in differentiation and growth inhibition of melanoma cells, as well as their susceptibility to immune clearance. GPER increased expression is correlated with reduced overall survival (OS) in melanoma patients

Genome Sequencing of Ancient Plant Remains: Findings, Uses and Potential Applications for the Study and Improvement of Modern Crops

The advent of new sequencing technologies is revolutionizing the studies of ancient DNA (aDNA). In the last 30 years, DNA extracted from the ancient remains of several plant species has been explored in small-scale studies, contributing to understand the adaptation, and migration patterns of important crops. More recently, NGS technologies applied on aDNA have opened up new avenues of research, allowing investigation of the domestication process on the whole-genome scale. Genomic approaches based on genome-wide and targeted sequencing have been shown to provide important information on crop evolution and on the history of agriculture. Huge amounts of next-generation sequencing (NGS) data offer various solutions to overcome problems related to the origin of the material, such as degradation, fragmentation of polynucleotides, and external contamination. Recent advances made in several crop domestication studies have boosted interest in this research area. Remains of any nature are potential candidates for aDNA recovery and almost all the analyses that can be made on fresh DNA can also be performed on aDNA. The analysis performed on aDNA can shed light on many phylogenetic questions concerning evolution, domestication, and improvement of plant species. It is a powerful instrument to reconstruct patterns of crop adaptation and migration. Information gathered can also be used in many fields of modern agriculture such as classical breeding, genome editing, pest management, and product promotion. Whilst unlocking the hidden genome of ancient crops offers great potential, the onus is now on the research community to use such information to gain new insight into agriculture

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer is a heterogeneous disease that still lacks specific therapeutic approaches. The identification of new biomarkers, predictive of the disease’s aggressiveness and pharmacological response, is a challenge for a more tailored approach in the clinical management of patients. Nerve growth factor, initially identified as a key factor for neuronal survival and differentiation, turned out to be a multifaceted molecule with pleiotropic effects in quite divergent cell types, including cancer cells. Many solid tumors exhibit derangements of the nerve growth factor and its receptors, including the tropomyosin receptor kinase A. This receptor is expressed in triple-negative breast cancer, although its role in the pathogenesis and aggressiveness of this disease is still under investigation. We now report that triple-negative breast cancer-derived MDAMB- 231 and MDA-MB-453 cells express appreciable levels of tropomyosin receptor kinase A and release a biologically active nerve growth factor. Activation of tropomyosin receptor kinase by nerve growth factor treatment positively affects the migration, invasion, and proliferation of triple-negative breast cancer cells. An increase in the size of triple-negative breast cancer cell spheroids is also detected. This latter effect might occur through the nerve growth factor-induced release of matrix metalloproteinase 9, which contributes to the reorganization of the extracellular matrix and cell invasiveness. The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses. Co-immunoprecipitation experiments in both cell lines show that nerve growth factor triggers the assembly of the TrkA/b1-integrin/FAK/Src complex, thereby activating several downstream effectors. GW441756 prevents the complex assembly induced by nerve growth factor as well as the activation of its dependent signaling. Pharmacological inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the silencing of b1-integrin, shows that the tyrosine kinases impinge on both proliferation and motility, while b1-integrin is needed for motility induced by nerve growth factor in triple-negative breast cancer cells. The present data support the key role of the nerve growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer and offer new hints in the diagnostic and therapeutic management of patients

A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

:Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone hormone antagonists

Communication between cells: exosomes as a delivery system in prostate cancer.

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database (https:// pubmed. ncbi. nlm. nih. gov) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented

Therapeutic potential of TRPM8 antagonists in prostate cancer.

Transient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers

Alien Domains Shaped the Modular Structure of Plant NLR Proteins

Plant innate immunity mostly relies on nucleotide-binding (NB) and leucine-rich repeat (LRR) intracellular receptors to detect pathogen-derived molecules and to induce defense responses. A multitaxa reconstruction of NB-domain associations allowed us to identify the first NB-LRR arrangement in the Chlorophyta division of the Viridiplantae. Our analysis points out that the basic NOD-like receptor (NLR) unit emerged in Chlorophytes by horizontal transfer and its diversification started from Toll/interleukin receptor-NB-LRR members. The operon-based genomic structure of Chromochloris zofingiensis NLR copies suggests a functional origin of NLR clusters. Moreover, the transmembrane signatures of NLR proteins in the unicellular alga C. zofingiensis support the hypothesis that the NLR-based immunity system of plants derives from a cell-surface surveillance system. Taken together, our findings suggest that NLRs originated in unicellular algae and may have a common origin with cell-surface LRR receptors