Single cell and bulk RNA sequencing identifies tumor microenvironment subtypes and chemoresistance-related IGF1⁺...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• The tumor microenvironment (TME) is crucial for gastric cancer (GC) prognosis and drug resistance.
• However, TME heterogeneity and its impact on therapeutic response in GC are not fully understood.

Purpose of the Study:

• To explore the heterogeneity of the GC TME using single-cell RNA sequencing.
• To identify distinct GC TME subtypes and their association with clinical outcomes and treatment response.
• To elucidate the role of cancer-associated fibroblasts (CAFs) in GC progression and chemoresistance.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of 50 primary GC samples.
• Nonnegative matrix factorization (NMF) to identify four GC TME subtypes.
• Pearson nearest-centroid classifier construction and validation in 1406 GC patients.
• Reclustering of fibroblasts to identify cancer-associated fibroblast (CAF) subtypes.
• RT-qPCR, immunofluorescence staining, and CellChat analysis for mechanistic insights.

Main Results:

• Four GC TME subtypes were identified, predicting differential responses to immunotherapy and chemotherapy.
• The ISG1 subtype showed increased fibroblast infiltration, heightened oncogenic pathways, and poor response to chemotherapy.
• Microsatellite instability-high (MSI-H) GCs exhibited immunological heterogeneity across TME subtypes.
• IGF1-overexpressing CAFs were associated with chemoresistance, GC recurrence, and induction of epithelial-mesenchymal transition (EMT) via IGF1-α6β4 integrin signaling.

Conclusions:

• Four TME-based subtypes with distinct clinical outcomes were identified in GC.
• IGF1+ CAFs contribute to poor clinical outcomes and chemoresistance in GC.
• These findings may guide individualized GC treatment strategies and identify novel therapeutic targets.