UCLA researchers have made new inroads into understanding germ cell tumors, a diverse and rare group of cancers that begin in germ cells — the cells that develop into sperm and eggs. The researchers developed a protocol to recreate germ cell tumor cells from stem cells and used the new model to study the genetics of the cancers. Their findings could point the way toward new drugs to treat germ cell tumors, which account for around 3 percent of all cases of childhood and adolescent cancers.
Embryonal carcinoma cells expressing the PRDM14 protein. Image: UCLA Broad Stem Cell Research Center/Elsevier
Germ cell tumors most often develop during embryonic development, in the testes and ovaries, but they also can occur in the spine, chest and brain when germ cells mistakenly migrate there. There are five subtypes of germ cell tumors: germinomas, embryonal carcinomas, yolk sac tumors, choriocarcinomas and teratomas. Each has its own unique properties, but most affect young children, adolescents and young adults.
“What makes this cancer really hard to study is that we think the disease begins in the womb and remains latent until after birth or during young adulthood,” says Amander Clark, PhD, chair of the Department of Molecular, Cell and Developmental Biology and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “That means we can’t easily isolate or study the very earliest stages of the disease in patients.”
Dr. Clark teamed up with pediatric cancer specialist Joanna Gell, MD (FEL ’16), who had become interested in germ cell tumors during her fellowship, while helping to care for a teenage girl with a hard-to-treat case. “The treatments we have are relatively effective in curing germ cell tumors, but they come with a whole host of serious side effects,” Dr. Gell says. For example, young adults treated with chemotherapy drugs could experience side effects such as heart disease, infertility or a higher risk for developing other cancers, she says.
Previous research suggested that a gene called PRDM14 may be involved in germ cell tumors; studies have identified mutations in PRDM14 that make men more susceptible to testicular cancer. Scientists know that the gene plays important roles in embryonic development, but because it is generally turned off in adult tissues, no PRDM14 protein is produced by healthy adult cells.
Drs. Clark and Gell coaxed human pluripotent stem cells, which can create any cell type in the body, to differentiate into germ cells at the embryonic stage of germ cell formation, when they are known as primordial germ cells. Then, they engineered the primordial germ cell-like cells to produce more PRDM14.
They found that higher levels of PRDM14 didn’t block the formation of primordial germ cell-like cells. However, those elevated levels did cause the primordial germ cell-like cells to begin proliferating more than usual and to not differentiate correctly, which could be a step toward cancer. The researchers also analyzed samples of germ cell tumors from patients and found evidence of PRDM14 protein in embryonal carcinomas, seminomas, intracranial germinomas and yolk sac tumors — but not in teratomas, which suggests that the protein could be a marker pathologists could use to better characterize the type of tumor.
“PRDM14 Is Expressed in Germ Cell Tumors with Constitutive Overexpression Altering Human Germline Differentiation and Proliferation,” Stem Cell Research, January 4, 2018
