Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibroinflammatory stroma with heterogeneous cancer-associated fibroblast (CAF) populations.
• The role of Hedgehog signaling in PDAC progression is contradictory, with potential roles in both promoting and restricting tumor growth.

Purpose of the Study:

• To investigate how Hedgehog pathway inhibition reprograms the PDAC microenvironment, considering the heterogeneity of CAFs.
• To elucidate the specific roles of Hedgehog signaling in different CAF subtypes.

Main Methods:

• Pharmacologic inhibition of the Hedgehog pathway.
• Gain- and loss-of-function genetic experiments.
• Cytometry by time-of-flight and single-cell RNA sequencing.

Main Results:

• Hedgehog signaling is activated in fibroblasts and elevated in myofibroblastic CAFs (myCAFs) compared to inflammatory CAFs (iCAFs).
• Sonic Hedgehog overexpression promotes PDAC growth; inhibition with LDE225 impairs tumor growth.
• Hedgehog inhibition decreases myCAF numbers and increases iCAF numbers, leading to reduced cytotoxic T cells and expanded regulatory T cells, indicating increased immunosuppression.

Conclusions:

• Hedgehog pathway inhibition significantly alters the composition of fibroblasts within the pancreatic cancer microenvironment.
• Modulation of CAF subtypes by Hedgehog inhibition impacts immune cell infiltration, promoting an immunosuppressive tumor microenvironment.