K-Ras and p53 Mouse Model With Molecular Characteristics of Human Rhabdomyosarcoma and Translational Applications

Authors

Kengo Nakahata
Brian W Simons
Enrico Pozzo
Ryan Shuck
Lyazat Kurenbekova
Zachary Prudowsky
Kshiti Dholakia
Cristian Coarfa
Tajhal D Patel
Lawrence A Donehower
Jason T Yustein

Publication Date

2-1-2022

Journal

Disease Models & Mechanisms

DOI

10.1242/dmm.049004

PMID

35174853

PMCID

PMC8844455

PubMedCentral® Posted Date

2-17-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Disease Models, Animal, Humans, Mice, Rhabdomyosarcoma, Sarcoma, Soft Tissue Neoplasms, Tumor Suppressor Protein p53, GEMM, Rhabdomyosarcoma, K-Ras, Syngeneic models

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of ∼65-70%. Thus, additional molecular insights and representative models are critical for identifying and evaluating new treatment modalities. Using MyoD-Cre-mediated introduction of mutant K-RasG12D and perturbations in p53, we developed a novel genetically engineered mouse model (GEMM) for RMS. The anatomic sites of primary RMS development recapitulated human disease, including tumors in the head, neck, extremities and abdomen. We confirmed RMS histology and diagnosis through Hematoxylin and Eosin staining, and positive immunohistochemical staining for desmin, myogenin, and phosphotungstic acid-Hematoxylin. Cell lines from GEMM tumors were established with the ability to engraft in immunocompetent mice with comparable histological and staining features as the primary tumors. Tail vein injection of cell lines had high metastatic potential to the lungs. Transcriptomic analyses of p53R172H/K-RasG12D GEMM-derived tumors showed evidence of high molecular homology with human RMS. Finally, pre-clinical use of these murine RMS lines showed similar therapeutic responsiveness to chemotherapy and targeted therapies as human RMS cell lines.

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