Stromal Hedgehog Signaling Is Associated with Favorable Outcomes in Pancreatic Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling Pathways

Background:

• Aberrant Hedgehog (Hh) signaling is implicated in various cancers, especially pancreatic ductal adenocarcinoma (PDAC), a stroma-rich tumor.
• Hh signaling promotes abundant stroma in PDAC, making it a therapeutic target, yet Hh antagonists have shown limited clinical success.
• The precise role of Hh signaling in tumor-stroma crosstalk within PDAC requires further elucidation to reassess Hh-targeted therapy efficacy.

Purpose of the Study:

• To investigate the role of Hh signaling in tumor-stroma crosstalk in pancreatic ductal adenocarcinoma (PDAC).
• To identify stromal targets responsive to Hh ligands and develop a stratification tool for patient selection in Hh-targeted therapy.
• To reassess the clinical potential of Hh-targeted therapy in a subset of PDAC patients.

Main Methods:

• Analysis of Hh ligand prognostic value in PDAC and its association with molecular subtypes.
• In vivo studies involving perturbation of Hh ligand expression in PDAC cells and co-injection with stromal cells (MEFs).
• Transcriptomic sequencing of co-cultures (PDAC cells and fibroblasts) treated with Hh-blocking antibodies to identify stromal response genes.

Main Results:

• Hh ligands are not directly prognostic in PDAC but are linked to the classical molecular subtype.
• Modulating Hh ligand expression in PDAC cells altered trans-signaling but not tumor growth in vivo.
• Co-injection with Smo-proficient MEFs significantly reduced xenograft growth, indicating stromal mediation of Hh effects.
• Transcriptomic analysis identified stromal genes responsive to Hh ligands, enabling patient stratification based on stromal response.

Conclusions:

• Hh-related effects on tumor growth in PDAC are primarily mediated through the tumor stroma.
• A subset of PDAC patients may benefit from Hh-targeted therapies.
• A developed stratification tool can guide the clinical application of Hh-targeted therapies in PDAC care.