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Targeting CAFs-Mediated Stromal Signaling in a Patient-Derived Organotypic Colorectal Tumor Model
Astha Lamichhane1, Prasiddha Guragain1, Jacob Heiss1
1Department of Biomedical Engineering, The University of Akron, Akron, Ohio.
Abstract:
Colorectal cancer, a significant cause of cancer-related mortality, often exhibits drug resistance, highlighting the need for improved tumor models to advance personalized drug testing and precision therapy. We generated organoids from primary colorectal cancer cells cultured through the conditional reprogramming technique, establishing a framework to perform short-term drug testing studies on patient-derived cells. To model interactions with stromal cells in the tumor microenvironment, we combined cancer cell organoids with carcinoma-associated fibroblasts, a cell type implicated in disease progression and drug resistance. Our organotypic models revealed that carcinoma-associated fibroblasts promote cancer cell proliferation and stemness primarily through hepatocyte growth factor-MET paracrine signaling and activation of cyclin-dependent kinases. Disrupting these tumor-stromal interactions reduced organoid size while limiting oncogenic signals and cancer stemness. Leveraging this tumor model, we identified effective drug combinations targeting colorectal cancer cells and their tumorigenic activities. Our study highlights a path to incorporate patient-derived cells and tumor-stromal interactions into a drug testing workflow that could identify effective therapies for individual patients.
Insights
This study developed patient-derived colorectal cancer organoids to test drugs. These models revealed how stromal cells drive cancer growth and identified effective drug combinations for precision therapy.
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.
