Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiation Therapy.

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying medulloblastoma resistance to treatment, we sought to uncover actionable targets and biomarkers that could help to refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence.

Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process.

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally.

The LIN28B-let-7-PBK pathway is essential for group 3 medulloblastoma tumor growth and survival.

Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin-28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease.

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment.

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.

Modeling human brain tumors in flies, worms, and zebrafish: From proof of principle to novel therapeutic targets.

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer.

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27).

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain.

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 genes. 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.

The U1 spliceosomal RNA is recurrently mutated in multiple cancers.

Cancers are caused by genomic alterations known as drivers. Hundreds of drivers in coding genes are known but, to date, only a handful of noncoding drivers have been discovered-despite intensive searching. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple types of cancer, although these mutations have only been found in protein-coding splicing factors such as splicing factor 3b subunit 1 (SF3B1).

Matrix metalloproteinase 9 contributes to gut microbe homeostasis in a model of infectious colitis.

Background: Inflammatory bowel diseases are associated with increased expression of zinc-dependent Matrix Metalloproteinase 9 (MMP-9). A stark dysregulation of intestinal mucosal homeostasis has been observed in patients with chronic inflammatory bowel diseases. We therefore sought to determine the contribution of MMP-9 to the pathogenesis of Citrobacter rodentium-induced colitis and its effects on gut microbiome homeostasis.