Life · 1 author, 2 centres
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This review examines how autophagy (a cellular self-digestion process) is linked to metastasis in neuroblastoma, a common childhood cancer. The author catalogs 11 molecular players and compounds that can either promote or suppress metastasis by modulating autophagy at different stages of cancer spread. Understanding these context-dependent relationships may lead to new biomarkers and treatments for metastatic neuroblastoma, which currently has poor outcomes.
**Background:** Neuroblastoma (NB) is a pediatric malignancy originating from the neural crest that accounts for nearly 10% of childhood cancers but disproportionately causes 15% of cancer-related deaths in children, equating to 1 in every 7000 live births. The median age of diagnosis is 18 months, and over half of patients present with metastasis at diagnosis, most commonly to lymph nodes, bone, and bone marrow. Metastasis accounts for most NB-related mortality, with patients showing bone marrow metastasis having an overall survival (OS) of 35.87% compared to 87.7% in those without bone marrow metastasis. Autophagy, a tightly regulated self-preservation mechanism facilitated by lysosomal autolysis, plays a dual role in cancer—suppressing tumor progression in early stages by removing damaged cellular components, but promoting metastasis in later stages by conferring resistance to cellular stressors such as nutrient deprivation, hypoxia, and loss of cell-matrix contact.
**Methods:** This is a narrative review that catalogs and summarizes evidence from the published literature on molecular players and compounds that link autophagy to metastasis specifically in neuroblastoma. The author searched for studies examining autophagy-related genes, non-coding RNAs, and small molecule compounds in NB cell lines, animal models, and patient samples. The review maps these factors to four arbitrary steps of the metastatic cascade: (1) in-situ primary tumor, (2) intravasation, (3) extravasation and seeding, and (4) colonization of distant sites. The author also searched clinicaltrials.gov for studies linking autophagy regulation with NB progression.
**Key Results:** The review identifies 11 molecular players or compounds linking autophagy to NB metastasis across several categories:
*Autophagy mediators:* ULK1 (UNC-51-like kinase 1) promotes anoikis resistance and metastasis. Inhibition of ULK1 using SBI-0206965 or dominant-negative ULK1 reduced autophagic flux, increased apoptosis (cleaved PARP and caspase-3), and reduced liver metastasis burden in NSG mouse models. dnULK1-SK-N-AS xenografts grew slower and showed prolonged survival in metastatic burden models.
*Oncogenic non-coding RNAs:* NORAD (lncRNA) was upregulated in NB tissues vs. matched healthy tissues and associated with advanced INSS stage and metastasis. NORAD knockdown reduced proliferation, migration, invasion, and doxorubicin resistance while increasing autophagy markers (Beclin 1, LC3-II/I ratio, ATG5) and apoptosis. NORAD exerts effects through the miR-144-3p/HDAC8 axis. hsa_circ_0013401 knockdown reduced proliferation and migration while promoting apoptosis and autophagy via the miR-195/PAK2 axis. SNHG16 knockdown reduced proliferation and migration through a regulatory loop with ATG5 and miR-542-3p.
*Tumor suppressor non-coding RNAs:* MEG3 (lncRNA) was negatively linked to NB INSS stage and positively linked to patient survival. Higher MEG3 expression correlated with greater 5-year event-free survival and overall survival. MEG3 overexpression suppressed proliferation, colony formation, migration, and invasion while reducing autophagy markers (Beclin 1, ATG3, ATG12, LC3-II/LC3-I ratio) through FOXO1 modulation (not mTOR). miR-34a targeted ATG5 and suppressed proliferation, apoptosis, metastasis, and autophagy.
*Compounds and small molecule inhibitors:* Isatin reduced invasion capacity of SH-SY5Y cells, inhibited mTOR phosphorylation, increased AMPK phosphorylation, and upregulated LC3-II and Beclin 1 while downregulating P62. Apatinib (VEGFR-2 inhibitor) reduced viability, proliferation, colony formation, and migration in BE(2)-M17, IMR-32, and SH-SY5Y cells, induced G0/G1 arrest and apoptosis, and increased LC3B-II/I ratio and ATG5 levels via PI3K/AKT/mTOR and MAPK/ERK pathways. Honokiol induced apoptosis and autophagy (increased LC3-II) and reduced migration via PI3K/Akt/mTOR pathway in neuro-2a cells.
**Clinical Implications:** The review highlights that autophagy plays a context-dependent dual role in NB metastasis—both promoting and suppressing cancer spread depending on the stage and molecular context. ULK1, NORAD, and other molecules may serve as potential biomarkers for predicting NB progression and metastasis, though this requires further preclinical and clinical validation. Currently, no clinical trials specifically linking autophagy regulation with NB progression were identified on clinicaltrials.gov. However, autophagy inhibitors such as 3-Methyladenine (3-MA) and Hydroxychloroquine (HCQ) have shown promise in preclinical studies for improving chemotherapy efficacy in NB. The author concludes that studying these molecules and their associated processes may lead to new treatment options and refinement of current therapeutics, ultimately improving quality of life for NB patients.