Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Suppress FGFR Inhibitor Efficacy

Area of Science:

• Oncology
• Cell Biology
• Molecular Medicine

Background:

• Obesity is linked to increased cancer aggressiveness and progression.
• Adipose tissue plays a role in enhancing tumor growth.
• Fibroblast growth factor receptor (FGFR) inhibitors are a recent therapeutic development.

Purpose of the Study:

• To identify mechanisms by which adipocyte precursor cells contribute to cancer progression.
• To investigate how urothelial carcinomas develop resistance to FGFR inhibitors like erdafitinib.
• To explore potential therapeutic interventions for FGFR inhibitor resistance.

Main Methods:

• Analysis of paracrine signaling between adipocyte precursor cells and urothelial carcinoma cells.
• Identification of key signaling molecules involved in resistance.
• Utilizing single-cell RNA sequencing data to analyze cell populations in human tumors.
• Testing the efficacy of pertuzumab in blocking the identified resistance pathway.

Main Results:

• Adipocyte precursor cells secrete neuregulin 1 (NRG1), activating HER3 signaling and conferring resistance to FGFR inhibitors.
• NRG1-mediated resistance can be overcome by pertuzumab, an antibody targeting the NRG1/HER3 axis.
• NRG1-expressing cells in human tumors resemble inflammatory cancer-associated fibroblasts (iCAFs), sharing gene signatures with adipose stromal cells (ASC) and fibro-adipogenic progenitors (FAP).

Conclusions:

• NRG1 secreted by adipocyte-derived cells is a novel mechanism of FGFR inhibitor resistance in urothelial carcinoma.
• The NRG1/HER3 axis represents a potential therapeutic target for overcoming resistance.
• The identified mechanism may represent a pan-cancer phenomenon contributing to tumor aggressiveness.