NNMT-associated metabolic-thromboinflammatory-immune co-activation in heterogeneous CTC clusters: a hypothesis-generating computational framework".

Authors

Jiayang Gong, Zhe Wang, Yun Shi, Minlan Ren, Tingting Li, Gang Li, Rui Peng

Published in

BMC cancer. Volume 26. Issue 1. Sep 10, 2026. Epub Sep 10, 2026.

Abstract

Heterogeneous circulating tumor cell (CTC) clusters interact with platelets, neutrophils, stromal cells, and immune cells, forming a protective state that may facilitate survival in the circulation and metastatic dissemination. Nicotinamide N-methyltransferase (NNMT) is associated with metabolic reprogramming, stromal activation, epithelial-mesenchymal plasticity, and immune suppression. However, its coordinated relationship with platelet/coagulation, neutrophil/ neutrophil extracellular trap (NET), and immune exhaustion programs in CTC-associated states has not been systematically evaluated. Therefore, we constructed a hypothesis-generating framework integrating mechanistic evidence, pan-cancer computational analyses, and single-cell transcriptomic analyses.
We performed a mechanistic evidence synthesis combined with TCGA PanCancer bulk RNA-seq analysis and cross-dataset evaluation of eight publicly available multi-cancer single-cell RNA-seq cohorts. Module scores were constructed for metabolic/EMT, platelet/coagulation, neutrophil/NET, immune checkpoint/exhaustion, and cytotoxic/NK cell programs. Correlation analyses across cancer types, feature-level pseudotime analysis, ligand- receptor mapping, and in silico perturbation simulations were applied to evaluate associations between NNMT and the composite tri-axial state. In addition, exploratory supervised machine learning models were used to determine whether axis-related features and ligand-receptor features could discriminate single CTCs from clustered or leukocyte-associated CTC states. Leave-one-cancer-out cross-validation was further used to assess the reproducibility of axis- associated survival risk across cancer types. No new experimental, animal, or clinical intervention data were generated.
Across 483,590 cells from eight publicly available single-cell datasets, NNMT expression was positively correlated with the composite tri-axial score across multiple cancer contexts. Feature-level pseudotime analysis indicated convergence of NNMT-associated metabolic, platelet/coagulation, neutrophil/NET, and immune exhaustion programs toward a common trajectory endpoint, although this analysis does not establish temporal causality. In silico NNMT perturbation preferentially implicated stromal and fibroblast-like populations as candidate responsive compartments. Ligand-receptor analyses further suggested an interconnected communication network involving CTC/epithelial and CAF/endothelial compartments, platelet/coagulation bridging, myeloid/NET recruitment, and downstream T/NK cell exhaustion.
These integrated findings support NNMT-associated metabolic-thromboinflammatory-immune co-activation as a candidate feature of heterogeneous CTC-associated states and provide mechanistic rationale for a "disaggregation-exposure-clearance" strategy combining αIIbβ3 inhibition, NNMT inhibition, and PD-1/PD-L1 blockade.

PMID:
42723032
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.

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