Targeting CAFs-Mediated Stromal Signaling in a Patient-Derived Organotypic Colorectal Tumor Model

Area of Science:

• Oncology
• Cancer Biology
• Drug Discovery

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality.
• Drug resistance in CRC necessitates better models for personalized therapy.
• Current models lack patient-derived cells and tumor microenvironment interactions.

Purpose of the Study:

• To develop patient-derived organoid models for colorectal cancer drug testing.
• To investigate the role of tumor-stromal interactions in CRC progression and drug resistance.
• To identify effective drug combinations for precision CRC therapy.

Main Methods:

• Generated patient-derived colorectal cancer organoids using conditional reprogramming.
• Co-cultured organoids with carcinoma-associated fibroblasts (CAFs) to model the tumor microenvironment.
• Analyzed HGF-MET signaling and Cyclin-Dependent Kinase (CDK) activation.
• Performed drug screening on the organotypic models.

Main Results:

• CAFs promote CRC cell proliferation and stemness via HGF-MET signaling and CDK activation.
• Disrupting tumor-stromal interactions reduced organoid growth and cancer stemness.
• Identified effective drug combinations targeting CRC cells and their tumorigenic activities.
• Established a framework for short-term drug testing on patient-derived cells.

Conclusions:

• Patient-derived organoids co-cultured with CAFs accurately model CRC tumor-stromal interactions.
• Targeting HGF-MET signaling and CDKs can overcome CAF-mediated drug resistance.
• This approach facilitates personalized drug testing and precision therapy for colorectal cancer.