Spatial gene expression profiling reveals the distinct microenvironment of tuberous sclerosis complex-associated angiomyolipoma

Abstract

The aim of this study was to characterize the transcriptional landscape of tuberous sclerosis complex-associated renal angiomyolipomas (TSC-AMLs) using spatial transcriptomics and to compare it with sporadic AMLs and renal cell carcinoma (RCC) to identify TSC-specific molecular features. Spatial gene expression analysis (CytAssist Visium) was performed on formalin-fixed, paraffin-embedded sections from one case each of TSC-AML, sporadic AML, and RCC. Unsupervised clustering revealed that TSC-AML and sporadic AML, unlike RCC, displayed triphasic tumor structures with vascular, smooth muscle, and adipose components expressing canonical perivascular epithelioid cell markers such as PMEL, MLANA, ACTB, and DES. TSC1 and TSC2 were downregulated, and mild upregulation of MTOR, MLST8, and RPTOR was observed, consistent with mTORC1 hyperactivation, whereas RCC showed broader pathway activation. Spatial pathway analysis indicated shared differentiation programs in smooth muscle regions but unique angiogenesis, extracellular matrix remodeling (Wnt and NABA matrisome), and lipid metabolic (PPAR signaling) enrichment in TSC-AML. Comparative profiling identified 42 genes uniquely upregulated in TSC-AML, including GRIA2, FABP4, and IL33, defining candidate TSC-AML–enriched features. Despite the single-case design, this pilot study provides hypothesis-generating insights into TSC-associated renal tumorigenesis and highlights potential biomarkers for future investigation.