Deciphering metabolic heterogeneity in retinoblastoma unravels the role of monocarboxylate transporter 1 in tumor progression.

BACKGROUND: Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. METHODS: The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. RESULTS: Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. CONCLUSIONS: This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.

Single-cell transcriptomics enable the characterization of local extension in retinoblastoma.

Retinoblastoma (RB) is the most prevalent ocular tumor of childhood, and its extraocular invasion significantly increases the risk of metastasis. Nevertheless, a single-cell characterization of RB local extension has been lacking. Here, we perform single-cell RNA sequencing on four RB samples (two from intraocular and two from extraocular RB patients), and integrate public datasets of five normal retina samples, four intraocular samples, and three extraocular RB samples to characterize RB local extension at the single-cell level. A total of 128,454 qualified cells are obtained in nine major cell types. Copy number variation inference reveals chromosome 6p amplification in cells derived from extraocular RB samples. In cellular heterogeneity analysis, we identified 10, 8, and 7 cell subpopulations in cone precursor like cells, retinoma like cells, and MKI67+ photoreceptorness decreased (MKI67+ PhrD) cells, respectively. A high expression level of SOX4 was detected in cells from extraocular samples, especially in MKI67+ PhrD cells, which was verified in additional clinical RB samples. These results suggest that SOX4 might drive RB local extension. Our study presents a single-cell transcriptomic landscape of intraocular and extraocular RB samples, improving our understanding of RB local extension at the single-cell resolution and providing potential therapeutic targets for RB patients.

Retinal microvasculature features in patients with migraine: a systematic review and meta-analysis.

Background: Migraine is a central nervous system disorder involving neuronal and vascular factors. The brain has a close anatomical relationship with retinal vessels and similar regulatory processes, and the retinal vascular system is the only in vivo vessel that can be directly visualized, while optical coherence tomography angiography (OCTA) is an advanced retinal vascular imaging technique. In this study, OCTA was used to study the retinal vascular density (VD) and foveal avascular zone (FAZ) in migraine patients, which provided a theoretical basis for its use as a candidate for rapid and non-invasive diagnosis of migraine. Methods: Published studies comparing retinal microvascular profiles between migraine patients and healthy controls were obtained by a comprehensive search of electronic databases. Nine studies were finally included, including 775 eyes (migraine group: 444 eyes, control group: 331 eyes). Pooled effect sizes were presented as standardized mean differences (SMDs) and 95% confidence intervals (CIs). Statistical analysis was performed using Review Manager software (version 5.30). Results: The combined results revealed that the superficial and deep macular whole enface VD (MWEVD) (superficial VD: SMD = -0.30, P = 0.0001; deep VD: SMD = -0.61, P = 0.02), superficial foveal VD (FVD) (SMD = -0.42, P = 0.03), deep parafoveal VD (PFVD) (SMD = -0.31, P = 0.002), and peripapillary VD (PVD) (SMD = -0.49, P = 0.002) were significantly reduced in migraine patients compared with healthy people. However, there was a significant increase in the area of the FAZ in migraine patients (SMD = 0.56, P < 0.0001). Conclusion: Migraine patients are prone to retinal microcirculation disorders, such as decreased blood vessel density and increased avascular area in the fovea. This provides a theoretical basis for OCTA as a candidate for rapid, non-invasive diagnosis of migraine.

CD38 deficiency protects the retina from ischaemia/reperfusion injury partly via suppression of TLR4/MyD88/NF-κB signalling.

PURPOSE: This study aimed to explore cellular localisation of CD38 in the retina and evaluate the role and potential mechanism of CD38 deficiency in retinal ischaemia/reperfusion (I/R) injury. METHODS: Six-to eight-week-old male CD38 knockout (KO) and wild-type mice in C57BL/6 background were used. Immunostaining was performed to determine the cellular localisation of CD38 in the retina. Haematoxylin and eosin staining and immunostaining of Brn3a were used to evaluate the retinal I/R injury. Western blotting was performed to detect toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), p-p65, ionised calcium-binding adapter molecule 1, Sirtuin1 (Sirt1), Ac-p65, and pro-inflammatory cytokines protein expression. RESULTS: CD38 was highly expressed in mouse retinal microglia and astrocytes/Müller cells. CD38 deficiency reduced I/R-induced retinal damage and retinal ganglion cell death. Following retinal I/R injury, TLR4, MyD88, nuclear factor-κB p-p65 (NF-κB p-p65), pro-inflammatory cytokines and CD38 protein levels were also upregulated. After I/R injury, retinal inflammation factors IL-1ß, IL-6, and TNF-α mRNA and protein levels were increased. IL-1ß, IL-6, and TNF-α were reduced in CD38 KO mice after I/R injury. Retinal I/R injury induced the activation of microglia, but this effect was also suppressed by KO of CD38. Additionally, retinal I/R induced a significant increase in Ac-p65 protein levels and decrease in Sirt1 protein levels, while this effect was greatly attenuated by KO of CD38. CONCLUSION: CD38 deficiency protects the retina from I/R injury by suppressing microglial activation partly via activating Sirt1-mediated suppression of TLR4/MyD88/NF-κB signalling.