Transcriptomic profiling of insulinomas reveals a new "low-endocrine" subtype with low YY1 expressions.

BACKGROUND Insulinoma is the most common functional pancreatic neuroendocrine tumors, typically originating from pancreatic β cells. However, the transcriptional heterogeneity and the regulatory role of transcription factor YY1 remain incompletely understood.

METHODS High-throughput bulk-RNA sequencing was conducted on insulinoma tumor samples. Unsupervised clustering algorithms were employed to identify molecular subtypes of insulinomas. YY1 mutation status was analyzed by whole-exome sequencing. Functional roles of YY1 were analyzed by Yy1-overexpression and knockdown in INS-1 cell line. Spatial transcriptomic characteristics of insulinoma were analyzed using Visium HD platform.

RESULTS Transcriptomic analysis identified two distinct expression patterns: a low-endocrine subtype and an endocrine subtype. The low-endocrine subtype was characterized by reduced PDX1 and insulin synthesis pathways, with an enrichment in exocrine-related functions. However, these two subtypes exhibited similar clinicopathological features. Notably, while YY1 mutation rates were comparable between the two subtypes, YY1 expression levels were significantly reduced in the low-endocrine subtype. Functional experiments demonstrated that Yy1 levels directly correlated with insulin production, as Yy1 overexpression in INS-1 cells markedly upregulated insulin processing genes and secretory pathways. Yy1 knockdown led to suppression of insulin. Furthermore, spatial transcriptomics confirmed that low-endocrine subtype possessed reduced insulin scores compared to the endocrine subtype.

CONCLUSION We found a low-endocrine subtype insulinoma with reduced YY1 expression and insulin synthesis transcriptomic signature. This highlights the transcriptomic heterogeneity of insulinomas.