From seconds to days: Neural plasticity viewed through a lipid lens.

Many adult neurons are dynamically remodeled across timescales ranging from the rapid addition and removal of specific synaptic connections, to largescale structural plasticity events that reconfigure circuits over hours, days, and months. Membrane lipids, including brain-enriched sphingolipids, play crucial roles in these processes. In this review, we summarize progress at the intersection of neuronal activity, lipids, and structural remodeling. We highlight how brain activity modulates lipid metabolism to enable adaptive structural plasticity, and showcase glia as key players in membrane remodeling. These studies reveal that lipids act as critical signaling molecules that instruct the dynamic architecture of the brain.

Glial control of sphingolipid levels sculpts diurnal remodeling in a circadian circuit.

Structural plasticity in the brain often necessitates dramatic remodeling of neuronal processes, with attendant reorganization of the cytoskeleton and membranes. Although cytoskeletal restructuring has been studied extensively, how lipids might orchestrate structural plasticity remains unclear. We show that specific glial cells in Drosophila produce glucocerebrosidase (GBA) to locally catabolize sphingolipids. Sphingolipid accumulation drives lysosomal dysfunction, causing gba1b mutants to harbor protein aggregates that cycle across circadian time and are regulated by neural activity, the circadian clock, and sleep. Although the vast majority of membrane lipids are stable across the day, a specific subset that is highly enriched in sphingolipids cycles daily in a gba1b-dependent fashion. Remarkably, both sphingolipid biosynthesis and degradation are required for the diurnal remodeling of circadian clock neurites, which grow and shrink across the day. Thus, dynamic sphingolipid regulation by glia enables diurnal circuit remodeling and proper circadian behavior.

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis.

Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.

Breaking Down Neighbors to Fuel Tumorigenesis.

Autophagy supports cell growth and survival autonomously by recycling intracellular proteins and/or organelles. Reporting in Nature, Katheder and colleagues (2017) find that tumors trigger non-autonomous autophagy in neighboring cells and distant organs, thus fueling tumor growth and metastasis. This opens new avenues for understanding and manipulating cancers through cell-cell communication.

Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia.

Cells dynamically interact throughout animal development to coordinate growth and deter disease. For example, cell-cell competition weeds out aberrant cells to enforce homeostasis. In Drosophila, tumorigenic cells mutant for the cell polarity gene scribble (scrib) are actively eliminated from epithelia when surrounded by wild-type cells. While scrib cell elimination depends critically on JNK signaling, JNK-dependent cell death cannot sufficiently explain scrib cell extirpation. Thus, how JNK executed cell elimination remained elusive. Here, we show that repulsive Slit-Robo2-Ena signaling exerts an extrusive force downstream of JNK to eliminate scrib cells from epithelia by disrupting E-cadherin. While loss of Slit-Robo2-Ena in scrib cells potentiates scrib tumor formation within the epithelium, Robo2-Ena hyperactivation surprisingly triggers luminal scrib tumor growth following excess extrusion. This extrusive signaling is amplified by a positive feedback loop between Slit-Robo2-Ena and JNK. Our observations provide a potential causal mechanism for Slit-Robo dysregulation in numerous human cancers.

Non-autonomous overgrowth by oncogenic niche cells: Cellular cooperation and competition in tumorigenesis.

Tumor progression is classically viewed as the Darwinian evolution of subclones that sequentially acquire genetic mutations and autonomously overproliferate. However, growing evidence suggests that tumor microenvironment and subclone heterogeneity contribute to non-autonomous tumor progression. Recent Drosophila studies revealed a common mechanism by which clones of genetically altered cells trigger non-autonomous overgrowth. Such "oncogenic niche cells" (ONCs) do not overgrow but instead stimulate neighbor overgrowth and metastasis. Establishment of ONCs depends on competition and cooperation between heterogeneous cell populations. This review characterizes diverse ONCs identified in Drosophila and describes the genetic basis of non-autonomous tumor progression. Similar mechanisms may contribute to mammalian cancer progression and recurrence.