Tumor-on-chip platforms for transport phenotyping: decoding CAF-driven barriers to drug delivery

Area of Science:

• Oncology
• Biophysics
• Biomaterials Science

Background:

• Solid tumors possess physical barriers hindering drug delivery, a key factor in therapeutic resistance.
• The tumor microenvironment (TME), remodeled by cancer-associated fibroblasts (CAFs), exhibits spatial heterogeneity impacting drug transport.
• Understanding extracellular matrix (ECM) remodeling and stromal mechanotransduction is crucial for overcoming drug delivery challenges.

Purpose of the Study:

• To investigate how CAF-driven ECM remodeling creates transport barriers within solid tumors.
• To explore the role of stromal mechanotransduction in governing therapeutic outcomes.
• To evaluate advanced microfluidic and tumor-on-chip (ToC) platforms for profiling CAF-driven transport phenotypes.

Main Methods:

• Analysis of CAF activation and subsequent ECM remodeling.
• Investigation of mechanical pathways of stromal mechanotransduction.
• Utilizing microfluidic and tumor-on-chip (ToC) platforms to mimic TME heterogeneity and assess drug transport.
• Development of "transport phenotyping" to characterize barrier properties.

Main Results:

• CAF-driven ECM remodeling leads to heterogeneous transport phenotypes that limit drug accessibility.
• These physical barriers dynamically influence therapeutic molecule delivery and efficacy.
• Advanced ToC platforms successfully replicate TME architecture, transport behavior, and therapeutic response.
• Transport barriers were identified as dynamically modifiable targets, not fixed obstacles.

Conclusions:

• Transport barriers are critical, modifiable targets in cancer therapy.
• "Transport phenotyping" offers a complementary approach to genomic profiling for personalized oncology.
• Integrating biophysics and precision medicine through transport phenotyping can improve treatment strategies for refractory tumors.