Persistent DNA strand breaks induce a CAF-like phenotype in normal fibroblasts

Area of Science:

• Oncology
• Molecular Biology
• Cancer Biology

Background:

• Cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis.
• Targeting CAFs is challenging due to a lack of selective elimination strategies.
• Pro-inflammatory microenvironments are implicated in CAF formation, but mechanisms are unclear.

Purpose of the Study:

• To elucidate the mechanisms by which pro-inflammatory stimulation drives fibroblast reprogramming into CAF-like cells.
• To identify therapeutic strategies for selectively eliminating CAF-like cells.
• To investigate the role of base excision repair (BER) in CAF generation.

Main Methods:

• Induction of CAF-like cells through prolonged pro-inflammatory stimulation.
• Assessment of DNA damage and repair pathways, specifically base excision repair (BER).
• Evaluation of ATF4-dependent gene expression changes during fibroblast reprogramming.
• Testing the efficacy of midostaurin in selectively eliminating *in vitro*-generated CAF-like cells.

Main Results:

• Prolonged pro-inflammatory stimulation leads to a deficiency in base excision repair (BER).
• Unrepaired DNA strand breaks trigger ATF4-dependent reprogramming of fibroblasts into CAF-like cells.
• Midostaurin selectively eliminates CAF-like cells exhibiting BER deficiency.
• Midostaurin treatment inhibits the pro-tumorigenic functions of CAF-like cells, including cancer cell growth and migration.

Conclusions:

• A pro-inflammatory microenvironment can induce CAF-like cells via BER deficiency and ATF4 activation.
• Midostaurin demonstrates selective efficacy against CAF-like cells with impaired DNA repair.
• Targeting BER-deficient CAFs with midostaurin represents a promising therapeutic approach for cancer treatment.