Sequential YAP1/FOSL1 silencing and epigenetic therapy to overcome stromal barriers in pancreatic cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes, largely due to its dense tumor microenvironment (TME) that impedes treatment.
• Cancer-associated fibroblasts (CAFs) within the TME promote tumor growth and create a stromal barrier, contributing to therapeutic resistance.

Purpose of the Study:

• To develop and evaluate a novel dual-therapy strategy to overcome therapeutic resistance in PDAC.
• To target the Hippo/MAPK pathways and histone deacetylation, crucial in PDAC progression and stromal interactions.

Main Methods:

• Developed liposomal siRNA complexes (lipoplexes) for targeted delivery of siRNA against YAP1 and FOSL1.
• Implemented a sequential treatment approach: initial YAP1/FOSL1 silencing followed by combination chemotherapy (entinostat and gemcitabine).
• Evaluated the therapeutic strategy in PDAC xenograft mouse models and 3D organoid cultures.

Main Results:

• Sequential silencing of YAP1 and FOSL1 significantly reduced stromal components in PDAC models.
• The approach enhanced the penetration of chemotherapy drugs into the tumor.
• Improved therapeutic efficacy was observed in both mouse models and organoids.

Conclusions:

• Targeting YAP1/FOSL1, key regulators of stromal remodeling, can overcome PDAC therapeutic resistance.
• Combining Hippo/MAPK pathway inhibition with epigenetic modulation (histone deacetylation inhibition) shows promise for PDAC treatment.
• This sequential dual-therapy strategy represents a potential advancement in improving outcomes for pancreatic cancer patients.