# Spatial omics study reveals molecular-cellular dynamics of tumor ecosystem in esophageal squamous-cell carcinoma initiation and progression

## TL;DR

This study uses spatial omics to track how tumors and their surroundings change during esophageal cancer development, revealing new insights into disease progression and potential treatment targets.

## Contribution

The study identifies novel molecular and cellular dynamics in esophageal squamous-cell carcinoma using spatial profiling and validates the role of O-GlcNAc transferase in tumor progression.

## Key findings

- Early-stage ESCC involves dysregulation of epidermal development and immune cell shifts.
- Late-stage ESCC features sustained PI3K/AKT pathway activation and disrupted tertiary lymphoid structures.
- O-GlcNAc transferase is upregulated in late stages, correlates with poor prognosis, and promotes tumor invasion.

## Abstract

Deciphering the molecular and cellular dynamics during esophageal squamous-cell carcinoma (ESCC) evolution is critical for elucidating the underlying disease mechanisms and devising rational targeted therapeutic strategies. Here, we perform digital spatial profiling on 32 tissue samples from 18 patients across different ESCC stages. At ESCC initiation, tumor cells undergo coordinated regulation of epidermal development and keratinocyte differentiation, accompanied by increased B cells and decreased T cells. In late stages, the phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) pathway is continuously upregulated, and tertiary lymphoid structures are dysregulated. We further verify these findings by multiplex immunofluorescence. Notably, the O-GlcNAc transferase gene, activated exclusively in late stages, correlates with poor prognosis, and its knockdown inhibits ESCC cell migration and invasion. In summary, this study unravels ESCC ecosystem evolution mechanisms via spatial omics, providing a roadmap for precision therapeutics.

•Digital spatial profiling of 32 tissue samples spanning from ESCC initiation to progression•Early-stage pathway dysregulation and immune cell alteration are characterized•PI3K/AKT activation and tertiary lymphoid structure dysfunction promote ESCC evolution•O-GlcNAc transferase drives tumor progression and correlates with poor prognosis

Digital spatial profiling of 32 tissue samples spanning from ESCC initiation to progression

Early-stage pathway dysregulation and immune cell alteration are characterized

PI3K/AKT activation and tertiary lymphoid structure dysfunction promote ESCC evolution

O-GlcNAc transferase drives tumor progression and correlates with poor prognosis

Liu et al. delineate ESCC molecular and cellular dynamics via spatial profiling of 32 tumors. Sustained activation of key pathways such as PI3K/AKT and dynamic immune microenvironment remodeling are identified during ESCC evolution. Functional assays confirm that OGT, upregulated in late-stage ESCC, drives tumor invasive potential.