Spatial transcriptome profiling identifies DTX3L and BST2 as key biomarkers in esophageal squamous cell carcinoma tumorigenesis

Dec 19, 2024Genome medicine

Gene activity patterns identify DTX3L and BST2 as important markers in esophageal squamous cell cancer development

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Abstract

Increased expression of in epithelial cells and in stromal cells correlates with the progression of early-stage esophageal squamous cell carcinoma (ESCC).

Spatial transcriptional changes and cell signaling pathways were associated with the progression of ESCC.
Macrophage infiltration increased from normal tissues through dysplasia to cancerous tissues.
The migration inhibitory factor (MIF)-CD74 axis may facilitate pro-tumor interactions between macrophages and epithelial cells.
Knockdown of DTX3L or BST2 resulted in reduced ESCC cell proliferation and migration.
Decreased M2 polarization of tumor-associated macrophages was observed following DTX3L or BST2 knockdown.

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BACKGROUND: Understanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC.

METHODS: Digital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted.

RESULTS: Spatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell-cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that expression in epithelial cells and expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages.

CONCLUSIONS: Spatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.

Key numbers

24 patients

Patient Cohort Size

Patients with pT1 ESCC analyzed for spatial transcriptomic profiling.

8.85

Increased Expression of

Mean expression score of in the stromal compartment categorized as high-expression.

M2 macrophages

Macrophage Infiltration Increase

Proportion of M2 macrophages increases during ESCC progression.

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Spatial transcriptome profiling identifies DTX3L and BST2 as key biomarkers in esophageal squamous cell carcinoma tumorigenesis

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