| First Author | Kodama M | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 21 | Pages | 5413-5424 |
| PubMed ID | 34475109 | Mgi Jnum | J:312347 |
| Mgi Id | MGI:6784126 | Doi | 10.1158/0008-5472.CAN-21-0356 |
| Citation | Kodama M, et al. (2021) Sleeping Beauty transposon mutagenesis identifies genes driving the initiation and metastasis of uterine leiomyosarcoma. Cancer Res |
| abstractText | Uterine leiomyosarcoma (ULMS) is a malignancy that arises from the uterine smooth muscle. Due to its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, Pten knockout, Kras mutant (PtenKO/Kras) mice. ULMS quickly developed in SB PtenKO/Kras mice, but not in Pten KO/Kras mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of Zfp217, was shown to be elevated in human ULMS compared to paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, while overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex-vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared to primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, while overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy. |
