Pulsed Low-Dose-Rate Chemoradiation Induces Stromal Reprogramming in Pancreatic CAF-Generated ECM: Quantification by...

Area of Science:

• Oncology
• Cancer Biology
• Radiotherapy Research

Background:

• Pancreatic cancer is lethal due to its complex desmoplastic tumor microenvironment (TME).
• Conventional chemoradiation has pro-tumoral effects on the TME.
• Novel therapeutic strategies are needed to overcome TME-driven resistance.

Purpose of the Study:

• To investigate pulsed low-dose-rate radiation (PLDR) as an alternative to conventional radiotherapy.
• To evaluate PLDR's impact on the TME in pancreatic cancer.
• To develop a novel method for quantifying stromal function in vitro.

Main Methods:

• Utilized a 3D cancer-associated fibroblast (CAF) functional unit culture system.
• Developed the Harmonic Output of Stromal Traits Factor (HOST-Factor) to assess stromal biomarkers.
• Modeled and altered TME behavior in vitro.

Main Results:

• PLDR combined with chemotherapy shifted the extracellular matrix (ECM) produced by CAFs.
• PLDR-treated CAFs produced ECMs that restricted further CAF activation.
• A shift in HOST-Factor values correlated with ECM's restrictive phenotype.

Conclusions:

• PLDR may restrict pancreatic cancer desmoplasia and enhance chemoradiotherapy efficacy.
• HOST-Factor offers a quantitative tool for assessing stromal function.
• Findings support ongoing clinical trials evaluating PLDR-based chemoradiation.