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Glioblastoma (GBM) is the most prevalent and malignant type of primary brain cancer. The rapid invasion and dissemination of tumor cells into the surrounding normal brain is a major driver of tumor recurrence, and long-term survival of GBM patients is extremely rare. Actin-rich cell membrane protrusions known as invadopodia can facilitate the highly invasive properties of GBM cells. Ion channels have been proposed to contribute to a pro-invasive phenotype in cancer cells and may also be involved in the invadopodia activity of GBM cells. GBM cell cytotoxicity screening of several ion channel drugs identified three drugs with potent cell killing efficacy: flunarizine dihydrochloride, econazole nitrate, and quinine hydrochloride dihydrate. These drugs demonstrated a reduction in GBM cell invadopodia activity and matrix metalloproteinase-2 (MMP-2) secretion. Importantly, the treatment of GBM cells with these drugs led to a significant reduction in radiation/temozolomide-induced invadopodia activity. The dual cytotoxic and anti-invasive efficacy of these agents merits further research into targeting ion channels to reduce GBM malignancy, with a potential for future clinical translation in combination with the standard therapy.

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Macrophages are a primary source of the growth factor Neuregulin-1 (NRG1), which has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues, and has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote the start of this isoform class from a myeloid-specific transcriptional start site (TSS). Long-read sequencing identified up to nine different NRG1-VII transcripts that show major structural differences from one another due to use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in human monocytes and tissue resident macrophages. Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. The size and structure of type VII isoforms suggests that they may be more diffusible than other NRG1 classes, however, the specific roles of type VII variants in tissue homeostasis and repair have not yet been determined.

Metastatic cancer is responsible for the overwhelming majority of cancer-related deaths with metastatic tumors being the most common neoplasms affecting the central nervous system. One of the major factors regulating tumor biology is the tumor microenvironment. However, little is known about the cellular and non-cellular composition of metastatic brain tumors and how tumor cell ontogeny influences the metastatic brain tumor microenvironment. By integrating multiplex immunohistochemistry and histopathological analysis to investigate composition and the spatial relationship between neoplastic cells, infiltrating and brain resident immune cells and the extracellular matrix, we demonstrate that metastatic brain tumors exhibit differences in ECM deposition, compared with the most common primary brain tumor type, glioblastoma, and that the dominant immune cell types in metastatic brain tumors are immunosuppressive macrophages, which preferentially localize to ECM-rich stromal regions.