# The Tumor‐to‐Endothelial Transfer of FTO Promotes Vascular Remodeling and Metastasis in Nasopharyngeal Carcinoma

## TL;DR

This study reveals how cancer stem cells in nasopharyngeal carcinoma transfer a protein called FTO to blood vessels, promoting cancer spread and suggesting new diagnostic and treatment approaches.

## Contribution

The study identifies a tumor-endothelial crosstalk mechanism driven by the NOTCH1–FTO–SPARC axis in nasopharyngeal carcinoma.

## Key findings

- NOTCH1⁺ CSCs secrete FTO via exosomes, which are taken up by endothelial cells.
- FTO disrupts endothelial tight junctions and increases SPARC protein levels, promoting metastasis.
- Inhibiting FTO with DAC51 suppresses metastasis in NPC mouse models.

## Abstract

Cancer stem‐like cells (CSCs) in nasopharyngeal carcinoma (NPC) exhibit heightened stemness, invasiveness, and resistance to therapy, posing significant challenges for diagnosis and treatment. How CSCs interact with the endothelium to drive vascular remodeling and metastasis remains unclear. Using spatially resolved multi‐omic profiling of clinical NPC samples and experimental validation, a tumor‐endothelial crosstalk mechanism is identified, driven by the NOTCH1–FTO–SPARC axis. Omics analysis reveals a distinct NOTCH1⁺ CSC subpopulation with enhanced tumorigenic potential. FTO, a direct transcriptional target and key effector of NOTCH1, promotes vascular remodeling and metastasis. Notably, NOTCH1⁺ tumors secreted FTO via exosomes, which are readily taken up by endothelial cells. Within recipient endothelial cells, accumulated FTO disrupts endothelial tight junctions by suppressing YTHDF2‐mediated m6A modification, stabilizing SPARC mRNA, and increasing SPARC protein levels. Inhibition of FTO with DAC51 significantly suppresses metastasis in NPC mouse models. Clinically, metastatic NPC patients show elevated levels of NOTCH1⁺ CSC‐CTCs (EPCAM⁺ EBNA1⁺ NOTCH1⁺ CD45−) and plasma FTO, suggesting their potential as blood‐based biomarkers for monitoring disease progression and treatment response. Overall, this study uncovers a non‐cell‐autonomous role of FTO in driving metastasis, with potential diagnostic and therapeutic utilities for NPC.

Integrated omics analysis of matched primary and liver metastatic NPC tumors reveals a unique NOTCH1+ CSC subpopulation exhibiting enhanced stemness properties and tumorigenic capacity. With in vitro and in vivo assays, exosomal transfer of tumor‐derived FTO from NOTCH1+ cells to the endothelium promotes vascular permeability and metastatic potential.