STC2+ Malignant Cell State Associated with EMT, Tumor Microenvironment Remodeling, and Poor Prognosis Revealed by...

Area of Science:

• Oncology
• Cancer Metabolism
• Tumor Microenvironment (TME)

Background:

• Colorectal cancer (CRC) heterogeneity involves alternative metabolic pathways, influenced by hypoxia and fructose, impacting the tumor microenvironment (TME).
• Understanding these metabolic adaptations and intercellular communication is crucial for identifying prognostic biomarkers and therapeutic targets in CRC.

Purpose of the Study:

• To identify specific malignant subpopulations in CRC utilizing alternative metabolic pathways.
• To characterize the intercellular signaling networks and spatial organization of these subpopulations within the TME.
• To develop a prognostic model based on hypoxia- and fructose metabolism-related genes (HFGs).

Main Methods:

• Integrative multi-omics approach combining bulk datasets, single-cell RNA sequencing, and spatial transcriptomics.
• Development of a prognostic model utilizing HFGs to delineate tumor cell subpopulations.
• Analysis of intercellular signaling networks and spatial organization of identified subpopulations.

Main Results:

• Identification of a stanniocalcin-2 positive (STC2+) malignant cell subset associated with poor prognosis in CRC.
• STC2+ cells exhibit increased epithelial-mesenchymal transition activity and act as a key signaling hub in the TME.
• Two distinct spatial ligand-receptor interactions involving STC2+ cells were identified: GDF15-TGFBR2 and MIF-CD74/CXCR4 pathways, targeting endothelial cells and macrophages, respectively.

Conclusions:

• A metabolically defined and spatially limited malignant cell state in CRC, characterized by elevated STC2 expression, was identified.
• This STC2+ subpopulation engages in significant immune-stromal interactions, contributing to TME remodeling.
• STC2+ malignant cells represent a functionally significant subpopulation and a potential therapeutic target for colorectal cancer, including liver metastases.