DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation

Area of Science:

• Developmental Biology
• Cancer Biology
• Stem Cell Research

Background:

• Epithelial stem cell differentiation and morphogenesis are critical for breast tissue development.
• Disruptions in these processes are implicated in breast cancer pathogenesis.
• Understanding the molecular mechanisms governing these processes is essential for identifying therapeutic targets.

Purpose of the Study:

• To investigate how individual stem cells differentiate and form complex breast tissue using a novel organoid model.
• To elucidate the role of discoidin domain receptor 1 (DDR1) in breast epithelial stem cell differentiation and morphogenesis.
• To identify the downstream targets and mechanisms regulated by DDR1 in this process.

Main Methods:

• Utilized a next-generation single-cell-derived organoid model for studying breast tissue development.
• Employed inhibition of discoidin domain receptor 1 (DDR1) and disruption of RUNX1 function.
• Performed mutational analyses on breast cancer patient data to assess the DDR1-RUNX1 signaling axis.

Main Results:

• Inhibition of DDR1 led to cells being trapped in a bipotent state, halting alveolar morphogenesis and luminal cell expansion.
• Disruption of RUNX1 function mirrored the DDR1 inhibition phenotype, indicating RUNX1 acts downstream of DDR1.
• DDR1 regulates RUNX1 activity by influencing its interaction and expression with its cofactor, core binding factor beta (CBFβ).
• Frequent alterations and co-occurring mutations in the DDR1-RUNX1 signaling axis were observed in breast cancer patients.

Conclusions:

• The DDR1-RUNX1 signaling pathway is a central regulator of breast epithelial stem cell differentiation and morphogenesis.
• Dysregulation of this pathway, particularly through mutations, is fundamentally linked to breast cancer development.
• These findings highlight the DDR1-RUNX1 axis as a potential therapeutic target for breast cancer.