Journal article
Development of a Cre-Inducible Rabl6a Transgenic Mouse Model That Enhances Sarcoma Growth In Vivo
Cancers, Vol.18(14), 2230
07/11/2026
DOI: 10.3390/cancers18142230
PMID: 42512296
Abstract
Background: Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that arise from Schwann cells and lack effective therapies. RABL6A is an oncogenic Rab-like GTPase whose expression is associated with worse survival in many human cancers. It is required for human MPNST cell survival, and its expression is dramatically increased in patient MPNSTs compared to benign precursor lesions. Methods: To model elevated expression of RABL6A in vivo, we developed transgenic mice expressing Cre-inducible Rabl6a. These Rabl6a-tg mice express the murine Rabl6a cDNA with a 5′ hemagglutinin [HA] epitope sequence downstream of a CMV enhancer and separated by a lox–stop–lox cassette. Double transgenic DhhCre; Rabl6a-tg mice were generated to achieve Schwann-cell specific Cre expression from the Desert hedgehog (Dhh) promoter. De novo MPNSTs were induced by CRISPR editing of Nf1, Ink4a, and Arf genes in the mouse sciatic nerve. Results: Cre-dependent expression of transgenic Rabl6a was verified at the mRNA and protein levels in Cre-positive mouse embryo fibroblasts and tissues. Increased Rabl6a expression in DhhCre; Rabl6a-tg mice had no effect on de novo MPNST initiation but significantly accelerated tumor progression relative to DhhCre control mice. The Rabl6a phenotype was associated with increased tumor angiogenesis but not proliferation. Interestingly, many MPNSTs in the DhhCre background exhibited varying levels of rhabdomyoblastic (RMB) features. That immature muscle cell phenotype is a hallmark of malignant Triton tumors, a rare histological variant of human MPNSTs associated with worse outcomes. Conclusions: These data provide direct evidence that Rabl6a is a functional driver of MPNSTs while establishing Rabl6a-tg mice as a suitable model for investigating Rabl6a’s role in other lethal RABL6A-high tumors.
Details
- Title: Subtitle
- Development of a Cre-Inducible Rabl6a Transgenic Mouse Model That Enhances Sarcoma Growth In Vivo
- Creators
- Ellen M. Voigt - University of IowaAlexandra L. Isaacson - University of IowaMariah R. Leidinger - University of IowaJames A. Goeken - University of IowaQuinn Hanigan - University of IowaDeng Fu GuoRachel M. Gasser - University of IowaMakenna Eadie - University of IowaIsabella Babor - University of IowaBenjamin W. Darbro - University of IowaWilliam Paradee - University of IowaKamal Rahmouni - University of IowaTian Zhao - University of IowaPatrick Breheny - University of Iowa, BiostatisticsEunhyeong Lee - Columbia University Irving Medical CenterMinah Kim - Columbia University Irving Medical CenterDavid K. Meyerholz - University of IowaMohammed Milhem - University of Iowa, Holden Comprehensive Cancer CenterRebecca D. Dodd - University of IowaDawn E. Quelle - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancers, Vol.18(14), 2230
- DOI
- 10.3390/cancers18142230
- PMID
- 42512296
- ISSN
- 2072-6694
- eISSN
- 2072-6694
- Publisher
- MDPI
- Grant note
- University of Iowa Fraternal Order of Eagles Diabetes Research Center National Institutes of Health: R01 NS119332, R01 HL162773, R01 HL172944 Department of Veterans Affairs: BX004249, BX006040
This work was supported by a grant, R01 NS119332 (MPI Darbro, Dodd, and Quelle), from the National Institutes of Health. Kamal Rahmouni is supported by the National Institutes of Health (R01 HL162773 and R01 HL172944), the Department of Veterans Affairs (Merit 1 I01 BX004249 and BLRD Research Career Scientist Award 1 IK6 BX006040), and the University of Iowa Fraternal Order of Eagles Diabetes Research Center.
- Language
- English
- Date published
- 07/11/2026
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Pathology; Iowa Neuroscience Institute; Biostatistics; Medical Genetics and Genomics; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Medicine Administration; Internal Medicine
- Record Identifier
- 9985182389902771
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