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.
Simplified
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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Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University ([2023]569) and was performed in accordance with the provisions of the Ethics Committee of Soochow University and the principles of the Declaration of Helsinki. All participants provided written informed consent to partake in this study. The animal experiment in this study was carried out following the guidelines established by the Care and Use of Laboratory Animals of Soochow University and was approved by the Animal Ethics Committee of the Soochow University Laboratory Animal Center (202406A0235). Consent for publications: Not applicable. Competing interests: The authors declare no competing interests.
PubMed
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