Spatial Proteomic Analysis Highlights Molecular Reprogramming in Optic Nerve Invasive Retinoblastoma

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Purpose: Molecular reprogramming at the interface between malignant and non-malignant contributes to heterogeneity and metastasis across various cancers. The optic nerve metastasis serves as a significant prognostic indicator for mortality in retinoblastoma (RB). This study seeks to unveil the molecular underpinnings of this phenomenon. Methods: We conducted a spatial proteomic analysis to delineate the heterogeneity within three RB samples exhibiting optic nerve invasion (ONI): case 1 and case 2 comparing the optic nerve invasive (ONI) group and the intraretinal group, and case 3 comparing tumor boundary and center. Data were archived in Mendeley Data [V1] (doi: 10.17632/xvtw7gmhzx.1; doi: 10.17632/mbsh6pcsnc.1). Immunofluorescence was performed to validate the expression patterns in additional RB samples of ONI versus the intraretinal group (n = 3 for each), and tumor boundary and center of neural metastasis (n = 4 for each). Results: Spatial proteomic analysis identified significant alterations in cholesterol metabolism in optic nerve-invasive lesions compared with intraretinal lesions. The boundary of the invasive RB at the optic nerve demonstrated an upregulation of anaplerotic reaction and oxidative respiration, along with a significant enhancement of keratin-mediated cytoskeletal remodeling. Moreover, the boundary lesions exhibit epigenetic remodeling, following decreased lysine methyltransferase 5C (KMT5C) levels, an important regulator of the epithelial/mesenchymal transition. Consistently, immunofluorescence analysis of pyruvate carboxylase (PC), keratin 17 (KRT17), and KMT5C substantiated distinct expression patterns in tumor boundary and center lesions. Conclusions: This study initially presents the spatial proteomic heterogeneity landscape in RB with ONI and uncovers its molecular reprogramming.

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