Spatial Heterogeneity, Stromal Phenotypes, and Therapeutic Vulnerabilities in Colorectal Cancer Peritoneal Metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis

Background:

• Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with poor prognosis.
• Understanding the molecular differences between primary tumors (PT) and PMs is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate molecular features differentiating primary CRC tumors from peritoneal metastases.
• To identify actionable therapeutic targets facilitating CRC transcoelomic dissemination and progression.

Main Methods:

• Multiomic profiling (whole-exome sequencing, bulk RNA sequencing, spatial profiling) of 227 CRC samples (56 PTs, 120 PMs).
• Orthogonal validation using multiplex immunohistochemistry (IHC).
• In vitro studies involving PAI-1 inhibition in CRC PM cell lines.

Main Results:

• Genomic alterations were similar between PTs and PMs, but transcriptomic profiles shifted towards a mesenchymal phenotype in PMs.
• A specific fibrotic and immune-infiltrated stromal phenotype (SC2) was identified, characterized by cancer-associated fibroblasts, memory B cells, M2 macrophages, and T-cell exhaustion.
• SC2 stroma correlated with poorer survival, high SERPINE-1 (PAI-1) expression, and enriched TGF-β signaling.
• PAI-1 inhibition reduced IL2-STAT5 and TGF-β pathways and induced cell death in CRC PM cell lines.

Conclusions:

• Distinct molecular signatures differentiate CRC PMs, highlighting the role of the tumor microenvironment.
• The identified SC2 stromal phenotype and PAI-1 represent actionable targets for CRC peritoneal metastasis.
• Targeting PAI-1 offers a potential therapeutic strategy to inhibit CRC PM progression.