Abstract B025: Metabolic rewiring and cellular crosstalk may drive grade transformation in pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (panNETs) undergo high-grade (HG) transformation often, with the liver being a common site for metastasis​. Surgical resection being considered as long-term outcomes for selected patients. However, recurrence and grade transformation remain potential significant challenges, with recurrence rates approaching 50–95%.1,2 Despite extensive whole exome analysis and construction of phylogenetic trees, we were unable to identify either a consistent genetic driver or any specific patterns of tumor transformation.2 We are also concerned that some of our treatments may inadvertently contribute to grade transformation. To assess the treatment effects, we performed pre- and post- trans arterial embolization bulk-transcriptome analysis, which revealed cell population shifts in panNETs that may be linked to grade transformation.4To explore cellular shifts within the liver tumor microenvironment during panNET progression, we performed single-cell RNA sequencing. The resulting data was processed using Seurat.v5. The clusters of panNET cells, fibroblasts, hepatocytes, and immune cells were annotated by known markers. Additionally, we distinguished malignant cells from a reference of immune cells, fibroblasts, and hepatocytes by InferCNV. To understand the tumor progression, we performed trajectory analysis using monocle3. Differential metabolic activity between the panNETs grades were assessed using the scMetabolism package. Cell-cell communication and related ligand-receptor pairs were inferred using CellChatDB. Our results revealed distinct transcriptional trajectories, with pseudotime analysis demonstrating a trajectory of tumor evolution from low-grade (LG) to HG states. HG tumors were enriched for proliferative and aggressive subclusters compared to LG cells. Metabolic profiling further highlighted grade-specific adaptations, with HG tumors showing enhanced oxidative phosphorylation and TCA cycle across tumor cells, whereas LG tumors displayed relatively lower metabolic activity. Notably, immune cells were found metabolically active in LG via glycolysis. Conversely, HG panNETs exhibit glucose depletion in immune cells and less active microenvironment. The CellChat analysis revealed distinct cellular communication patterns in panNET grade. For instance, in HG tumors, signaling was primarily mediated between fibroblasts and panNET cells, with Glu-(SLC1A2+GLS)-GRM7 as the dominant ligand–receptor pair. In LG tumors, major interactions occurred among immune cells, hepatocytes, and panNET cells, with Glu-(SLC1A3+GLS)-GRIK2 representing the highest contributor. The results suggest that metabolic rewiring, altered intercellular signaling, and transcriptional plasticity underlie progression from LG to HG disease. Reference: 1. Spolverato etal J Gastrointest Surg. 2017, 21(12):2039-2047 2. Mayo etal Ann Surg Onc. 2011, 18(13):3657-65. 3. Singh et al. Early ... Margie and Robert E. Peterson Neuroendocrine Tumor Research Symposium. 2023. 4. Singh et al. Post... Margie and Robert E. Peterson Neuroendocrine Tumor Research Symposium.2023 Citation Format: Himanshu N. Singh, Chenyang Zhan, Jessica C. Puzzuoli, Elias-Ramzey Karnoub, Jungeui Hong, Nitya Raj, Olca Basturk, Zeynep Tarcan, Christine A. Iacobuzio, Etay Ziv. Metabolic rewiring and cellular crosstalk may drive grade transformation in pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B025.