Endosomal actin branching, fission and receptor recycling require FCHSD2 recruitment by MICAL-L1.

Endosome fission is required for the release of carrier vesicles and the recycling of receptors to the plasma membrane. Early events in endosome budding and fission rely on actin branching to constrict the endosomal membrane, ultimately leading to nucleotide hydrolysis and enzymatic fission. However, our current understanding of this process is limited, particularly regarding the coordination between the early and late steps of endosomal fission. Here we have identified a novel interaction between the endosomal scaffolding protein, MICAL-L1, and the human homolog of the Drosophila Nervous Wreck (Nwk) protein, FCH and double SH3 domains protein 2 (FCHSD2). We demonstrate that MICAL-L1 recruits FCHSD2 to the endosomal membrane, where it is required for ARP2/3-mediated generation of branched actin, endosome fission and receptor recycling to the plasma membrane. Since MICAL-L1 first recruits FCHSD2 to the endosomal membrane, and is subsequently responsible for recruitment of the ATPase and fission protein EHD1 to endosomes, our findings support a model in which MICAL-L1 orchestrates endosomal fission by connecting between the early actin-driven and subsequent nucleotide hydrolysis steps of the process.

Neuroblastoma: Emerging trends in pathogenesis, diagnosis, and therapeutic targets.

Neuroblastoma (NB) accounts for about 13% of all pediatric cancer mortality and is the leading cause of pediatric cancer death for children aged 1 to 5 years. NB, a developmental malignancy of neural ganglia, originates from neural crest-derived cells, which undergo a defective sympathetic neuronal differentiation due to genomic and epigenetic aberrations. NB is a complex disease with remarkable biological and genetic variation and clinical heterogeneity, such as spontaneous regression, treatment resistance, and poor survival rates. Depending on its severity, NB is categorized as high-risk, intermediate-risk, and low-risk., whereas high-risk NB accounts for a high infant mortality rate. Several studies revealed that NB cells suppress immune cell activity through diverse signaling pathways, including exosome-based signaling pathways. Exosome signaling has been shown to modulate gene expression in the target immune cells and attenuate the signaling events through non-coding RNAs. Since high-risk NB is characterized by a low survival rate and high clinical heterogeneity with current intensive therapies, it is crucial to unravel the molecular events of pathogenesis and develop novel therapeutic targets in high-risk, relapsed, or recurrent tumors in NB to improve patient survival. This article discusses etiology, pathophysiology, risk assessment, molecular cytogenetics, and the contribution of extracellular vesicles, non-coding RNAs, and cancer stem cells in the tumorigenesis of NB. We also detail the latest developments in NB immunotherapy and nanoparticle-mediated drug delivery treatment options.

Immune checkpoint molecules in neuroblastoma: A clinical perspective.

High-risk neuroblastoma (NB) is challenging to treat with 5-year long-term survival in patients remaining below 50% and low chances of survival after tumor relapse or recurrence. Different strategies are being tested or under evaluation to destroy resistant tumors and improve survival outcomes in NB patients. Immunotherapy, which uses certain parts of a person's immune system to recognize or kill tumor cells, effectively improves patient outcomes in several types of cancer, including NB. One of the immunotherapy strategies is to block immune checkpoint signaling in tumors to increase tumor immunogenicity and anti-tumor immunity. Immune checkpoint proteins put brakes on immune cell functions to regulate immune activation, but this activity is exploited in tumors to evade immune surveillance and attack. Immune checkpoint proteins play an essential role in NB biology and immune escape mechanisms, which makes these tumors immunologically cold. Therapeutic strategies to block immune checkpoint signaling have shown promising outcomes in NB but only in a subset of patients. However, combining immune checkpoint blockade with other therapies, including conjugated antibody-based immunotherapy, radioimmunotherapy, tumor vaccines, or cellular therapies like modified T or natural killer (NK) cells, has shown encouraging results in enhancing anti-tumor immunity in the preclinical setting. An analysis of publicly available dataset using computational tools has unraveled the complexity of multiple cancer including NB. This review comprehensively summarizes the current information on immune checkpoint molecules, their biology, role in immune suppression and tumor development, and novel therapeutic approaches combining immune checkpoint inhibitors with other therapies to combat high-risk NB.