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Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on [ASCL1.sup.lo] and [ASCL1.sup.hi] GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in [ASCL1.sup.lo] GSCs. In contrast, in [ASCL1.sup.hi] GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in [ASCL1.sup.lo] GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype-restricted cancer stem cells., Introduction Glioblastoma multiforme (GBM) is the most common malignant brain cancer in adults (1, 2). Consistent with its progressive nature, GBM remains significantly refractory to current therapeutic strategies (3, 4). [...]

Emerging evidence suggests that intracellular molecules and organelles transfer between cells during embryonic development, tissue homeostasis and disease. We and others recently showed that transplanted and host photoreceptors engage in bidirectional transfer of intracellular material in the recipient retina, a process termed material transfer (MT). We used cell transplantation, advanced tissue imaging approaches, genetic and pharmacologic interventions and primary cell culture to characterize and elucidate the mechanism of MT. We show that MT correlates with donor cell persistence and the accumulation of donor‐derived proteins, mitochondria and transcripts in acceptor cells in vivo. MT requires cell contact in vitro and is associated with the formation of stable microtubule‐containing protrusions, termed photoreceptor nanotubes (PhNTs), that connect donor and host cells in vivo and in vitro. PhNTs mediate GFP transfer between connected cells in vitro. Furthermore, interfering with PhNT outgrowth by targeting Rho GTPase‐dependent actin remodelling inhibits MT in vivo. Collectively, our observations provide evidence for horizontal exchange of intracellular material via nanotube‐like connections between neurons in vivo. Synopsis: Transplanted photoreceptors extend cellular protrusions that contact host photoreceptors and mediate the transfer of transcripts, protein, and mitochondria. The understanding of this phenomenon could transform the cell based therapeutical strategy for certain types of retinal degeneration. The degree of GFP transfer to the host retina depends on the number of surviving transplanted donor cellsTransferred cargo include transcripts, nuclear, cytosolic, membrane associated proteins and organellesMaterial transfer is contact‐dependent and associated with the formation of microtubule containing protrusions that connect donor and acceptor cells after transplantationPhotoreceptor nanotube (PhNT) outgrowth and material transfer are regulated by Rho GTPase‐dependent actin cytoskeletal remodelling [ABSTRACT FROM AUTHOR]