K-Ras and p53 mouse model with molecular characteristics of human rhabdomyosarcoma and translational applications

Area of Science:

• Oncology
• Genetics
• Animal Models

Background:

• Rhabdomyosarcoma (RMS) is the most frequent pediatric soft tissue sarcoma, with survival rates around 65-70%.
• Improved molecular understanding and accurate models are essential for developing novel therapeutic strategies against RMS.

Purpose of the Study:

• To create and characterize a novel genetically engineered mouse model (GEMM) for rhabdomyosarcoma.
• To assess the model's fidelity to human RMS in terms of tumor development, histology, and molecular characteristics.

Main Methods:

• Development of a GEMM using MyoD-Cre mediated K-RasG12D mutation and p53 perturbation.
• Histological and immunohistochemical analyses (H&E, desmin, myogenin, PTAH) for RMS confirmation.
• Establishment and characterization of GEMM-derived cell lines, including engraftment and metastatic potential studies.
• Transcriptomic analysis to compare GEMM tumors with human RMS.

Main Results:

• The GEMM accurately recapitulated the anatomic sites of human RMS, including head, neck, extremities, and abdomen.
• GEMM-derived cell lines exhibited RMS histology and high metastatic potential to the lungs upon tail vein injection.
• Transcriptomic data revealed significant molecular homology between GEMM-derived tumors and human RMS.
• Murine RMS lines demonstrated comparable therapeutic responsiveness to chemotherapy and targeted agents as human RMS cell lines.

Conclusions:

• The developed GEMM serves as a valuable preclinical tool for studying rhabdomyosarcoma.
• This model facilitates the investigation of RMS pathogenesis and the evaluation of novel therapeutic interventions.