Skeletal stem cell lineages in osteosarcoma and bone metastasis

Area of Science:

• Skeletal biology and oncology

Background:

• Skeletal stem cells (SSCs) are crucial for bone development, homeostasis, and regeneration.
• SSCs are also implicated in bone tumor development and metastasis.
• Fibroblast growth factor receptor 3 (Fgfr3)-positive endosteal stem cells represent a distinct SSC population.

Purpose of the Study:

• To synthesize current knowledge on SSCs and their lineage derivatives.
• To provide a framework for understanding SSC roles in bone homeostasis and cancer.
• To highlight Fgfr3+ endosteal stem cells as potential origin cells for osteosarcoma.

Main Methods:

• Comprehensive review of lineage-tracing studies, genetically engineered mouse models, and bone tumor models.
• Integration of findings on SSC hierarchy and differentiation.
• Analysis of Fgfr3-creER; Trp53fl/fl mouse models for osteosarcoma induction.

Main Results:

• Fgfr3+ endosteal stem cells differentiate into osteoblasts and CXCL12-expressing stromal cells that support the hematopoietic niche.
• Trp53 deletion in Fgfr3+ endosteal stem cells rapidly induces osteosarcoma.
• SSC-derived stromal cells can differentiate into cancer-associated fibroblasts that promote metastasis, angiogenesis, and immunosuppression.

Conclusions:

• Fgfr3+ endosteal stem cells are candidate cells of origin for osteosarcoma.
• SSC-derived lineages play a dual role in both initiating and progressing bone tumors.
• Targeting endosteal niches may offer novel therapeutic strategies for bone malignancies.