Abstract: FR-PO222
Influence of the Extracellular Matrix on the Tumor Microenvironment and Cancer Progression
Session Information
- Onconephrology: Immunotherapy Nephrotoxicity and Assessment of GFR
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1700 Onconephrology
Authors
- Petrosyan, Astgik, University of Southern California, Los Angeles, California, United States
- Koos, David S., Children's Hospital Los Angeles, Los Angeles, California, United States
- Thornton, Matthew Edward, University of Southern California, Los Angeles, California, United States
- Aguiari, Paola, Children's Hospital Los Angeles, Los Angeles, California, United States
- Villani, Valentina, Children's Hospital Los Angeles, Los Angeles, California, United States
- Fernandez, G. Esteban, Children's Hospital Los Angeles, Los Angeles, California, United States
- Grubbs, Brendan, University of Southern California, Los Angeles, California, United States
- De Filippo, Roger E., Children's Hospital Los Angeles, Los Angeles, California, United States
- Perin, Laura, University of Southern California, Los Angeles, California, United States
Background
This study explores how the extracellular matrix (ECM) in the tumor microenvironment influences cell behavior in Wilms Tumor (WT), a pediatric kidney cancer. We compare the effects of 2D cultures and cancerous versus normal kidney ECM on cellular activities using decellularization techniques, two-photon excited fluorescence (TPEF) microscopy, and transcriptomics.
Methods
We optimized the decellularization technique for normal kidney and WT samples and characterized the decellularized matrices (dECM) with second-harmonic generation (SHG) microscopy (up to 700um in depth) and immunohistochemistry. Protein expression in WT dECM was compared to normal kidney dECM using Oncology Arrays. Bulk transcriptomics was performed on WT and normal human kidney (hFK) nephron progenitors cultured in 2D and on normal kidney and WT dECM scaffolds for 21 days.
Results
Imaging of tumor ECM revealed structural differences, with denser, elongated fibers in the outer layers and mesh-like structures deeper inside. Tumor ECM showed higher expression of oncoproteins (e.g., CEA, PSA-ACT), receptors (e.g., IGF 1R, IGF-II), and markers of cell adhesion and migration (e.g., PDGFR alpha). Cells cultured on tumor dECM exhibited upregulation of genes related to immune response, cancer progression, and metastasis, whereas 2D cultures primarily showed genes involved in basic cellular processes. Cellular behavior and transcriptomic profiles were significantly altered when cultured on tumor versus normal ECM, with tumor ECM promoting proliferation pathways and inhibiting differentiation pathways. Normal cells seeded on tumor ECM activated cancer development pathways and inhibited apoptotic pathways.
Conclusion
This study underscores the critical role of the ECM in influencing cancer cell behavior. These findings are crucial for developing physiologically relevant in vitro tumor models and identifying new therapeutic targets that focus on the ECM in cancer treatment.
Funding
- Private Foundation Support