Development of mouse models of angiosarcoma driven by p53.

Area of Science:

• Oncology
• Vascular Biology
• Cancer Genetics

Background:

• Angiosarcomas are rare vascular tumors with limited treatment options and poor outcomes.
• The lack of effective preclinical models hinders the development of new therapeutic strategies for angiosarcoma.
• Understanding the cell of origin and genetic drivers is crucial for developing targeted therapies.

Purpose of the Study:

• To develop and characterize novel autochthonous mouse models of angiosarcoma.
• To investigate the role of p53 loss in endothelial cells and pericytes in angiosarcoma development.
• To establish a reliable preclinical model for evaluating potential angiosarcoma treatments.

Main Methods:

• Utilized Cre-lox recombination systems (Cdh5-Cre and Pdgfrb-Cre) to induce Trp53 deletion or mutation in specific cell types.
• Generated mice with homozygous deletion (Trp53(fl/fl)) or mutant expression (Trp53(R172H/R172H)) of p53 in endothelial cells and pericytes.
• Assessed tumor development, incidence, and survival rates in genetically engineered mouse models.
• Evaluated the utility of passaging tumor fragments for a more rapid and consistent angiosarcoma model.

Main Results:

• Cdh5-Cre driven Trp53 deletion in endothelial cells resulted in 100% penetrance of angiosarcomas with a median survival of 325 days.
• Expression of mutant p53 (R172H) in endothelial cells led to thymic lymphomas, not angiosarcomas.
• Pdgfrb-Cre driven Trp53 deletion primarily caused lymphomas and soft tissue sarcomas, but not angiosarcomas.
• Pdgfrb-Cre driven mutant p53 expression induced angiosarcomas in 75% of mice, often concurrently with lymphomas.
• Passaging of Cdh5-Cre, Trp53(fl/fl) angiosarcoma tumor fragments created a more rapid and consistent preclinical model.

Conclusions:

• Loss of p53 in VE-cadherin-expressing endothelial cells is sufficient to induce angiosarcoma in a genetically engineered mouse model.
• Different p53 mutations (null vs. mutant) and cell-of-origin targeting (endothelial vs. pericyte) yield distinct tumor types.
• A novel, highly penetrant, and rapidly progressing autochthonous mouse model of angiosarcoma has been developed.
• This model, particularly the passaged tumor fragment system, is amenable to preclinical studies for novel angiosarcoma therapies.