Myofibroblasts Induce Neuroplasticity to Promote Pancreatic Inflammation and Cancer Progression

Area of Science:

• Oncology
• Neuroscience
• Gastroenterology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) involves nerve remodeling, but the role of cancer-associated fibroblasts (CAFs) is unclear.
• Autonomic nerves influence PDAC cells, yet their interaction with CAFs in neural remodeling remains uninvestigated.

Purpose of the Study:

• To investigate the role of cancer-associated fibroblasts (CAFs) in neural remodeling within pancreatic cancer.
• To elucidate the mechanisms by which CAFs and the nervous system interact to promote PDAC progression.

Main Methods:

• Analysis of thick tissue sections to identify innervation patterns near myofibroblastic CAFs (myCAFs) in Pancreatic Intraepithelial Neoplasms (PanINs).
• In vitro studies using myofibroblast cultures to assess the effects of norepinephrine.
• In vivo studies involving sympathetic nerve depletion in PDAC models.
• Utilizing a chemogenetic model to examine fibroblast-specific α1-adrenergic signaling.

Main Results:

• Dense neo-innervation was observed near myCAFs in preinvasive PanINs.
• myCAFs were found to produce axon guidance molecules, recruiting sympathetic nerves.
• Sympathetic nerve activation of myofibroblasts was confirmed in vitro, and nerve depletion impaired tumor growth in vivo.
• Fibroblast-specific α1-adrenergic signaling exacerbated pancreatic inflammation and neoplasia.

Conclusions:

• Sympathetic nerves promote pancreatitis and PDAC by co-opting myofibroblasts and myCAFs as disease amplifiers.
• CAF subtype-specific stromal interactions represent potential therapeutic targets for PDAC.
• The study reveals a novel mechanism of PDAC progression involving sympathetic nerve-CAF crosstalk.