Mapping metabolic reprogramming dynamics across pancreatic neuroendocrine tumor cell differentiation at single-cell...

Area of Science:

• Oncology
• Metabolic Biology
• Genomics

Background:

• The metabolic switch between oxidative phosphorylation (OXPHOS) and aerobic glycolysis is crucial in tumor biology.
• Dynamic regulation of this switch during pancreatic neuroendocrine tumor (pNET) cell differentiation is poorly understood at single-cell resolution.

Purpose of the Study:

• To investigate the metabolic reprogramming of pNET cells during differentiation using single-cell RNA sequencing.
• To identify key molecular regulators and signaling pathways involved in metabolic state transitions in pNETs.

Main Methods:

• Analysis of publicly available single-cell RNA sequencing data from pNETs.
• Pseudotime ordering, dimensionality reduction, and co-expression network construction for metabolic state estimation.
• Validation of gene expression patterns using qRT-PCR and ELISA in pNET cell lines.

Main Results:

• Identified ten transcriptionally distinct cell clusters, including dominant PT-like tumor cells.
• Characterized three metabolic states: OXPHOS-high, Mixed, and Glycolysis-high, varying across PT sub-clusters.
• Discovered MALAT1 as a key discriminative feature and identified prominent intercellular signaling axes (e.g., TGFB1, SPP1, VEGFA).

Conclusions:

• pNET cell metabolism shifts from OXPHOS-dominant to glycolysis-dominant states along the differentiation trajectory.
• MALAT1, ATP5F1B, PKM, and NDUFS1 are identified as key regulatory nodes in this metabolic reprogramming.
• Targeting the OXPHOS-to-glycolysis transition presents a potential therapeutic strategy for pancreatic neuroendocrine tumors.