Dissecting the Spatial and Single-Cell Transcriptomic Architecture of Cancer Stem Cell Niche Driving Tumor...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Biology

Background:

• Cancer stem cells (CSCs) are crucial drivers of therapeutic resistance and progression in gastric cancer (GC).
• The specific transcriptional programs governing the CSC niche's role in tumor stemness and progression remain incompletely understood.

Purpose of the Study:

• To elucidate the transcriptional landscape of the CSC niche in gastric cancer.
• To identify key interactions and signaling pathways that maintain CSC stemness and drive tumor progression.
• To uncover novel therapeutic targets for overcoming drug resistance in gastric cancer.

Main Methods:

• Spatial and single-cell RNA sequencing performed on 32 human gastric mucosa tissues across malignancy stages.
• Analysis of transcriptional trajectories from mature gastric chief cells to CSC states.
• Investigation of CSC interactions with immune cells (T cells, M2 macrophages) and cancer-associated fibroblasts (iCAFs).

Main Results:

• Identified a transcriptional trajectory from mature cells to CSCs, involving EGFR and WNT pathway activation.
• Demonstrated CSC interactions with immunosuppressive immune cells and iCAFs, forming a niche that promotes tumorigenesis and stemness.
• Discovered that iCAF-derived amphiregulin (AREG) upregulates SOX9, promoting stemness and drug resistance via the AREG-ERBB2 axis.

Conclusions:

• The CSC niche in gastric cancer is characterized by specific cellular interactions and signaling pathways that drive stemness and progression.
• Amphiregulin (AREG) signaling represents a critical mechanism for maintaining CSC stemness and conferring drug resistance.
• Targeting the CSC niche, particularly the AREG-ERBB2 axis, holds promise for developing novel therapeutic strategies against gastric cancer.