Single-cell Transcriptome Analysis Identifies Senescent Osteocytes as Contributors to Bone Destruction in Breast...

Area of Science:

• Oncology
• Bone Biology
• Cellular Senescence

Background:

• Breast cancer bone metastases lead to significant morbidity and mortality by increasing fracture risk.
• Tumor cell colonization of bone reprograms the microenvironment, disrupting bone remodeling and causing lesions.
• The impact of this reprogramming on matrix-embedded osteocytes has been poorly understood.

Approach:

• Single-cell RNA sequencing identified osteocytes with senescence and pro-osteoclastogenic markers in metastatic bone.
• Multiplex in situ hybridization and AI analysis detected osteocyte senescence markers in mice and patients.
• In vitro and ex vivo models demonstrated breast cancer cells induce osteocyte senescence and osteoclastogenesis.

Key Points:

• Osteocytes in breast cancer bone metastases exhibit premature senescence and a senescence-associated secretory phenotype (SASP) that promotes bone destruction.
• Senescent osteocytes express senescence markers, telomere dysfunction, and p16.
• Breast cancer cells directly induce osteocyte senescence and enhance their osteoclastogenic potential.

Conclusions:

• Osteocyte senescence is a pathological response to breast cancer cell colonization, contributing to bone destruction.
• Senolytic treatment cleared senescent cells, suppressed bone resorption, and preserved bone mass in preclinical models.
• Targeting osteocyte senescence represents a promising therapeutic strategy for breast cancer bone metastases.