Macrophage-mediated myelin recycling fuels brain cancer malignancy.

Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype.

Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment.

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy.

Double-modified, thio and methylene ATP analogue facilitates wound healing in vitro and in vivo.

Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP analogue-alpha-thio-beta,gamma-methylene-ATP as a potential therapeutic agent for a skin regeneration. For the better understanding of structure-activity relationship, beside tested ATP analogues, the appropriate single-modified derivatives of target compound, such as alpha-thio-ATP and beta,gamma-methylene-ATP, were also tested in the context of their involvement in the activation of ATP-dependent purinergic signaling pathway via the P2Y2 receptor.

Lactate secreted by glycolytic conjunctival melanoma cells attracts and polarizes macrophages to drive angiogenesis in zebrafish xenografts.

Conjunctival melanoma (CoM) is a rare but potentially lethal cancer of the eye, with limited therapeutic option for metastases. A better understanding how primary CoM disseminate to form metastases is urgently needed in order to develop novel therapies. Previous studies indicated that primary CoM tumors express Vascular Endothelial Growth Factor (VEGF) and may recruit pro-tumorigenic M2-like macrophages.

Simultaneous targeting of AMPK and mTOR is a novel therapeutic strategy against prostate cancer.

Metastatic colonization by circulating cancer cells is a highly inefficient process. To colonize distant organs, disseminating cancer cells must overcome many obstacles in foreign microenvironments, and only a small fraction of them survives this process. How these disseminating cancer cells cope with stress and initiate metastatic process is not fully understood.

Zebrafish Patient-Derived Xenograft Model as a Preclinical Platform for Uveal Melanoma Drug Discovery.

Uveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there is a great need to harness the limited material available from primary tumors and metastases for advanced research and preclinical drug screening. We established a platform to isolate, preserve, and transiently recover viable tissues, followed by the generation of spheroid cultures derived from primary UM.

Novel Treatments of Uveal Melanoma Identified with a Synthetic Lethal CRISPR/Cas9 Screen.

Currently, no systemic treatment is approved as the standard of care for metastatic uveal melanoma (UM). mTOR has been evaluated as a drug target in UM. However, one of the main limitations is dose reduction due to adverse effects.

Photosubstitution in a trisheteroleptic ruthenium complex inhibits conjunctival melanoma growth in a zebrafish orthotopic xenograft model.

data are rare but essential for establishing the clinical potential of ruthenium-based photoactivated chemotherapy (PACT) compounds, a new family of phototherapeutic drugs that are activated ligand photosubstitution. Here a novel trisheteroleptic ruthenium complex [Ru(dpp)(bpy)(mtmp)](PF) ([2](PF), dpp = 4,7-diphenyl-1,10-phenanthroline, bpy = 2,2'-bipyridine, mtmp = 2-methylthiomethylpyridine) was synthesized and its light-activated anticancer properties were validated in cancer cell monolayers, 3D tumor spheroids, and in embryonic zebrafish cancer models. Upon green light irradiation, the non-toxic mtmp ligand is selectively cleaved off, thereby releasing a phototoxic ruthenium-based photoproduct capable notably of binding to nuclear DNA and triggering DNA damage and apoptosis within 24-48 h.

Establishment of Embryonic Zebrafish Xenograft Assays to Investigate TGF-β Family Signaling in Human Breast Cancer Progression.

Transforming growth factor-β (TGF-β) family members have pivotal functions in controlling breast cancer progression, acting not only on cancer cells but also on other cells within the tumor microenvironment. Here we describe embryonic zebrafish xenograft assays to investigate how TGF-β family signaling controls breast cancer cell intravasation, extravasation and regulates tumor angiogenesis. Fluorescently mCherry-labeled breast cancer cells are injected in the perivitelline space or Duct of Cuvier of Tg (fli:EGFP) transgenic Casper zebrafish embryos, in which the zebrafish express enhanced green fluorescent protein in the entire vasculature.

Ortho- and Ectopic Zebrafish Xeno-Engraftment of Ocular Melanoma to Recapitulate Primary Tumor and Experimental Metastasis Development.

There are currently no animal models for metastatic ocular melanoma. The lack of metastatic disease models has greatly hampered the research and development of novel strategies for the treatment of metastatic ocular melanoma. In this protocol we delineate a quick and efficient way to generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma, using retro-orbital orthotopic and intravascular ectopic cell engraftment, respectively.

The Receptor Tyrosine Kinase RON and Its Isoforms as Therapeutic Targets in Ewing Sarcoma.

The receptor tyrosine kinase (RTK) RON is linked to an aggressive metastatic phenotype of carcinomas. While gaining interest as a therapeutic target, RON remains unstudied in sarcomas. In Ewing sarcoma, we identified RON among RTKs conferring resistance to insulin-like growth factor-1 receptor (IGF1R) targeting.

Zebrafish Microenvironment Elevates EMT and CSC-Like Phenotype of Engrafted Prostate Cancer Cells.

To visually and genetically trace single-cell dynamics of human prostate cancer (PCa) cells at the early stage of metastasis, a zebrafish (ZF) xenograft model was employed. The phenotypes of intravenously transplanted fluorescent cells were monitored by high-resolution, single-cell intravital confocal and light-sheet imaging. Engrafted osteotropic, androgen independent PCa cells were extravasated from caudle vein, invaded the neighboring tissue, proliferated and formed experimental metastases around caudal hematopoietic tissue (CHT) in four days.

TLD1433 Photosensitizer Inhibits Conjunctival Melanoma Cells in Zebrafish Ectopic and Orthotopic Tumour Models.

The ruthenium-based photosensitizer (PS) TLD1433 has completed a phase I clinical trial for photodynamic therapy (PDT) treatment of bladder cancer. Here, we investigated a possible repurposing of this drug for treatment of conjunctival melanoma (CM). CM is a rare but often deadly ocular cancer.

Light-Triggered Cancer Cell Specific Targeting and Liposomal Drug Delivery in a Zebrafish Xenograft Model.

Cell-specific drug delivery remains a major unmet challenge for cancer nanomedicines. Here, light-triggered, cell-specific delivery of liposome-encapsulated doxorubicin to xenograft human cancer cells in live zebrafish embryos is demonstrated. This method relies on light-triggered dePEGylation of liposome surfaces to reveal underlying targeting functionality.

A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis.

Metastasis is a main cause of death in prostate cancer (PCa). To dissect the molecular cues from cancer cell-microenvironment interaction that drive metastatic cascade, bone metastatic PCa cells were intravenously implanted into zebrafish embryos and mice tibia forming metastatic lesions. Transcriptomic analysis showed an elevated expression of stemness genes, pro-inflammatory cytokines and TGF-β family member Activin A in the cancer cells at metastatic onset in both animal models.

miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo.

Background: Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa.

Diverse and cancer type‑specific roles of the p53 R248Q gain‑of‑function mutation in cancer migration and invasiveness.

Gain‑of‑function (GOF) mutations in the TP53 gene lead to acquisition of new functions by the mutated tumor suppressor p53 protein. A number of the over‑represented 'hot spot' mutations, including the ones in codons 175, 248 or 273, convey GOF phenotypes. Such phenotypes may include resistance to chemotherapeutics or changes in motility and invasiveness.

Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish.

Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis.

Human melanoma brain metastases cell line MUG-Mel1, isolated clones and their detailed characterization.

Melanoma is a leading cause of high mortality that frequently spreads to the brain and is associated with deterioration in quality and quantity of life. Treatment opportunities have been restricted until now and new therapy options are urgently required. Our focus was to reveal the potential heterogeneity of melanoma brain metastasis.

Therapeutic Targeting of CD146/MCAM Reduces Bone Metastasis in Prostate Cancer.

Prostate Cancer is the most common cancer and the second leading cause of cancer-related death in males. When prostate cancer acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting melanoma cell adhesion molecule (MCAM; CD146) with a mAb for the treatment of lytic prostate cancer bone metastasis.

Animal Models of Breast Cancer Bone Metastasis.

This chapter is designed to provide a comprehensive overview outlining the different in vivo models available for research into breast cancer bone metastasis. The main focus is to guide the researcher through the methodological processes required to establish and utilize these models within their own laboratory. These detailed methods are designed to enable the acquisition of accurate and meaningful results that can be used for publication and future translation into clinical benefit for women with breast cancer-induced bone metastasis.

Correction to: A p53/miR-30a/ZEB2 axis controls triple negative breast cancer aggressiveness.

Since publication of the article, the authors were notified by ATCC that the cell line HCC1395 (ATCC® CRL-2324™ Lot 62235652) suffered a "low level of cell line cross-contamination" with another cell line.

Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model.

Chronic liver damage leads to the onset of fibrogenesis. Rodent models for liver fibrosis have been widely used, but are less suitable for screening purposes. Therefore the aim of our study was to design a novel model for liver fibrosis in zebrafish embryos, suitable for high throughput screening.

Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis.

Purpose: Cancer-associated fibroblasts (CAF) are a major component of the colorectal cancer tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through TGF-β signaling pathway. We investigated whether the TGF-β family coreceptor endoglin is involved in CAF-mediated invasion and metastasis.

Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target.

Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy.