Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity.

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2+ tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of ß-catenin. Piezo2 knockout reverses WNT/ß-catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer.

Channeling Force in the Brain: Mechanosensitive Ion Channels Choreograph Mechanics and Malignancies.

Force is everywhere. Through cell-intrinsic activities and interactions with the microenvironment, cells generate, transmit, and sense mechanical forces, such as compression, tension, and shear stress. These forces shape the mechanical properties of cells and tissues. Akin to how balanced biochemical signaling safeguards physiological processes, a mechanical optimum is required for homeostasis. The brain constructs a mechanical optimum from its cellular and extracellular constituents. However, in brain cancer, the mechanical properties are disrupted: tumor and nontumoral cells experience dysregulated solid and fluid stress, while tumor tissue develops altered stiffness. Mechanosensitive (MS) ion channels perceive mechanical cues to govern ion flux and cellular signaling. In this review, we describe the mechanical properties of the brain in healthy and cancer states and illustrate MS ion channels as sensors of mechanical cues to regulate malignant growth. Targeting MS ion channels offers disease insights at the interface of cancer, neuroscience, and mechanobiology to reveal therapeutic opportunities in brain tumors.

Chloride intracellular channel 1 cooperates with potassium channel EAG2 to promote medulloblastoma growth.

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma growth in xenograft and genetically engineered mouse models. Mechanistically, CLIC1 enriches to the plasma membrane during mitosis and cooperates with potassium channel EAG2 at lipid rafts to regulate cell volume homeostasis. CLIC1 deficiency is associated with elevation of cell/nuclear volume ratio, uncoupling between RNA biosynthesis and cell size increase, and activation of the p38 MAPK pathway that suppresses proliferation. Concurrent knockdown of CLIC1/EAG2 and their evolutionarily conserved channels synergistically suppressed the growth of human medulloblastoma cells and Drosophila melanogaster brain tumors, respectively. These findings establish CLIC1 as a molecular dependency in rapidly dividing medulloblastoma cells, provide insights into the mechanism by which CLIC1 regulates tumorigenesis, and reveal that targeting CLIC1 and its functionally cooperative potassium channel is a disease-intervention strategy.

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Bioactive, nutritional composition, heavy metal and pesticide residue of four Chinese jujube cultivars.

This study aims to conduct a detailed investigation on four cultivars grown in northwest China, concentrating on the analysis of the bioactive contents, nutrients, heavy metal concentrations, and pesticide residue contents. Those Chinese jujubes consist of 51.99-71.75% edible part, 82.35-89.63% carbohydrates, 4.43-6.01% protein, 0.48-0.63% lipid, 2.80-4.80% polysaccharide, 45.64-88.97 mg/100 g ascorbic acid, 132.16-196.58 mg/100 g phenolics and 101.17-132.04 mg/100 g flavonoids in dry matter. In those four Chinese jujube cultivars, sulfur amino acids are the first limiting amino acids for adults, and aromatic amino acids are for children. The amount of heavy metal and pesticide residue concentrations in those jujubes was way below the limit. All four cultivars were found to have different nutritional values except for the carbohydrates; they had higher rates of carbohydrates and polysaccharide than those previously reported ones from Eastern China; and they are a better source for carbohydrates, vitamin C and functional amino acids.

Small RNAs control sodium channel expression, nociceptor excitability, and pain thresholds.

To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that inflammatory pain was attenuated or abolished. Inflammatory mediators failed to enhance excitability of Nav1.8+ sensory neurons from null mutant mice. Acute noxious input into the dorsal horn of the spinal cord was apparently normal, but the increased input associated with inflammatory pain measured using c-Fos staining was diminished. Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8+ sensory neurons that may regulate nociceptor gene expression.