Daniel W. Fults

The seismic effects of the coronavirus disease 2019 (COVID-19) pandemic on human activity impacted the healthcare industry profoundly. Healthcare providers and administrators struggled heroically not only to treat surging numbers of patients afflicted by virus infection, but also to maintain high-quality medical practice standards for all other diseases. Adding to these challenges was the pressing need to protect front-line medical workers from contracting the virus themselves. Nonurgent medical services were by necessity suspended during the tumultuous pandemic period, and many patients had to postpone needed medical treatments. The outbreak of COVID-19 put the neuro-oncology community in a state of high alarm because hospital critical care resources, so essential for brain tumor patients, were heavily used to combat the life-threatening pulmonary complications of coronavirus infection. When the pandemic was in full swing, no one knew whether the quality of neuro-oncology care would be adversely affected. Advocating for maintaining the most effective neuro-oncology practice standards, spokespersons for several professional organizations published guidelines for treating brain tumor patients during the pandemic, which emphasized maximum safe resection as soon as possible after radiographic identification of high-grade gliomas.^1–3

A surprising theme that has emerged from sequencing the cancer genome is that mutations in genes encoding histone proteins are very common. Histones bind DNA to form bead-like structures (nucleosomes) along the DNA strand. At each nucleosome, the DNA double helix wraps around a complex of four pairs of core histone proteins (H2A, H2B, H3, and H4), spanned by a single linker protein (H1). Histones are no longer considered to be simply DNA-packaging proteins but instead are understood to be dynamic regulators of gene expression.¹ Covalent modifications of histones, such as addition and removal of methyl and acetyl groups on lysine residues, induce conformational...

Daniel W Fults; Marauding Monocytes, Macrophages, and Microglia in Gliomas, Neuro-Oncology, , noaa185, https://doi.org/10.1093/neuonc/noaa185

Leptomeningeal dissemination (LMD) is the defining pattern of metastasis for medulloblastoma. Although LMD is responsible for virtually 100% of medulloblastoma deaths, it remains the least well-understood part of medulloblastoma pathogenesis. The fact that medulloblastomas rarely metastasize outside the CNS but rather spread almost exclusively to the spinal and intracranial leptomeninges has fostered the long-held belief that medulloblastoma cells spread directly through the CSF, not the bloodstream. In this paper the authors discuss selected molecules for which experimental evidence explains how the effects of each molecule on cell physiology contribute mechanistically to LMD. A model of medulloblastoma LMD is described, analogous to the invasion–metastasis cascade of hematogenous metastasis of carcinomas. The LMD cascade is based on the molecular themes that 1) transcription factors launch cell programs that mediate cell motility and invasiveness and maintain tumor cells in a stem-like state; 2) disseminating medulloblastoma cells escape multiple death threats by subverting apoptosis; and 3) inflammatory chemokine signaling promotes LMD by creating an oncogenic microenvironment. The authors also review recent experimental evidence that challenges the belief that CSF spread is the sole mechanism of LMD and reveal an alternative scheme in which medulloblastoma cells can enter the bloodstream and subsequently home to the leptomeninges.

A highly aggressive subgroup of the pediatric brain tumor medulloblastoma is characterized by overexpression of the proto-oncogene c-Myc, which encodes a transcription factor that normally maintains neural progenitor cells in an undifferentiated, proliferating state during embryonic development. Myc-driven medulloblastomas typically show a large-cell anaplastic (LCA) histological pattern, in which tumor cells display large, round nuclei with prominent nucleoli. This subgroup of medulloblastoma is therapeutically challenging because it is associated with a high rate of metastatic dissemination, which is a powerful predictor of short patient survival times. Genetically engineered mouse models have revealed important insights into the pathogenesis of medulloblastoma and served as preclinical testing platforms for new therapies. Here we report a new mouse model of Myc-driven medulloblastoma, in which tumors arise in situ after retroviral transfer and expression of Myc in Nestin-expressing neural progenitor cells in the cerebella of newborn mice. Tumor induction required concomitant loss of Tp53 or overexpression of the antiapoptotic protein Bcl-2. Like Myc-driven medulloblastomas in humans, the tumors induced in mice by Myc + Bcl-2 and Myc − Tp53 showed LCA cytoarchitecture and a high rate of metastatic dissemination to the spine. The fact that Myc − Tp53 tumors arose only in Tp53 ^−/− mice, coupled with the inefficient germline transmission of the Tp53-null allele, made retroviral transfer of Myc + Bcl-2 a more practical method for generating LCA medulloblastomas. The high rate of spinal metastasis (87 % of brain tumor–bearing mice) will be an asset for testing new therapies that target the most lethal aspect of medulloblastoma.

Leptomeningeal dissemination (LMD), the metastatic spread of tumor cells via the cerebrospinal fluid to the brain and spinal cord, is an ominous prognostic sign for patients with the pediatric brain tumor medulloblastoma. The need to reduce the risk of LMD has driven the development of aggressive treatment regimens, which cause disabling neurotoxic side effects in long-term survivors. Transposon-mediated mutagenesis studies in mice have revealed numerous candidate metastasis genes. Understanding how these genes drive LMD will require functional assessment using in vivo and cell culture models of medulloblastoma. We analyzed two genes that were sites of frequent transposon insertion and highly expressed in human medulloblastomas: Arnt (aryl hydrocarbon receptor nuclear translocator) and Gdi2 (GDP dissociation inhibitor 2). Here we show that ectopic expression of Arnt and Gdi2 promoted LMD in mice bearing Sonic hedgehog (Shh)-induced medulloblastomas. We overexpressed Arnt and Gdi2 in a human medulloblastoma cell line (DAOY) and an immortalized, nontransformed cell line derived from mouse granule neuron precursors (SHH-NPD) and quantified migration, invasiveness, and anchorage-independent growth, cell traits that are associated with metastatic competence in carcinomas. In SHH-NPD cells. Arnt and Gdi2 stimulated all three traits. In DAOY cells, Arnt had the same effects, but Gdi2 stimulated invasiveness only. These results support a mechanism whereby Arnt and Gdi2 cause cells to detach from the primary tumor mass by increasing cell motility and invasiveness. By conferring to tumor cells the ability to proliferate without surface attachment, Arnt and Gdi2 favor the formation of stable colonies of cells capable of seeding the leptomeninges.