A Novel Mouse Model To Elucidate The Origins And Therapeutic Sensitivity Of Testicular Germ Cell Tumors
Pierpont, Timothy Michael
Testicular germ cell tumors (TGCTs) are the most common malignancy among young men. These cancers are exquisitely sensitive to genotoxic chemotherapies, even after distant metastasis. A better understanding of the mechanisms underlying this chemosensitivity could improve treatments for more chemoresistant cancers. Because TGCTs arise from germ cells and contain cells with prominent pluripotent stem cell features, we hypothesized that specialized DNA damage response (DDR) properties associated with pluripotent stem cells might underlie their exquisite chemosensitivity. To test this hypothesis and to further elucidate the biology of these cancers, we generated a novel mouse model of malignant TGCTs. Tumorigenesis was induced by simultaneous cre mediated Pten inactivation and KrasG12D activation controlled by Stra8-cre, a germ cell-specific cre recombinase. Approximately 75% of mice with both Pten and Kras alterations developed grossly apparent teratocarcinoma by five weeks of age. These tumors harbored both a teratoma component and malignant embryonal carcinoma (EC), a totipotent cancer stem cell (CSC) identified diagnostically by expression of OCT4, NANOG, and SOX2. Early neoplasms were also detected in testes as early as postnatal-day 3, and only 1-2 tumor initiation sites were observed per testis, suggesting that tumor induction occurred prenatally. Indeed, lineage tracing analyses identified Cre-mediated excision in rare, isolated clusters of germ cells as early as 12.5 post fertilization. Treatment of TGCT bearing mice with genotoxic chemotherapeutics resulted in significantly increased survival and reduced tumor burden. Most significantly, the EC cells were selectively depleted from the primary tumors of treated mice. These findings suggested these CSCs were uniquely sensitive to genotoxic chemotherapy, which may help explain why genotoxic drugs are so efficacious in treating this disease. To better understand how the CSCs were responding to chemotherapeutics, we established two EC cell lines from our mouse model. Both EC cell lines retained their ability to reproduce teratocarcinomas and exhibited increased chemosensitivity compared to differentiated cells derived from the same cell lines. Using these in vivo and in vitro models, ongoing research will continue to identify more specific mechanisms underlying the chemosensitivity in these cancers.
Cellular biology; Molecular biology; Cancer Stem Cell; Cisplatin; Embryonal Carcinoma; Germ Cell; Teratocarcinoma; TGCT; Biology
Weiss, Robert S.
Tumbar, Tudorita; Schimenti, John C.
Biochem, Molec & Cell Biology
PHD of Biochem, Molec & Cell Biology
Doctor of Philosophy
dissertation or thesis