Creating cancer for the greater good

CHAPEL HILL, N.C.—While most people think of stem-cell research in terms of making those cells become useful new tissues for improving the health of a human body, researchers at the University of North Carolina (UNC) at Chapel Hill School of Medicine are taking a different approach. Isolating normal stem cells that form the developing placenta, they then gave them the same properties of stem cells associated with a particularly deadly type of breast cancer—all to better understand aggressive cancers and fight them more effectively.

"We changed only one amino acid in normal tissue stem cells, trophoblast stem cells," explains Dr. Gary Johnson, professor and chair of pharmacology at UNC, member of the UNC Lineberger Comprehensive Cancer Center and senior author of the study that appeared online May 6 in the journal Cell Stem Cell. "While they maintained their self-renewal, these mutant stem cells had properties very similar to what people predict in cancer stem cells: they were highly mobile and highly invasive. No one has ever isolated a stem cell like that."

Normally, he says, trophoblasts—a kind of epithelial stem cell—play an important role in forming placental tissue, undergoing a conversion to tissue-like cells and traveling to the site in the uterus where they belong, reverting to a noninvasive tissue cell.

"But the mutant trophoblast stem cells made in our lab, which would normally invade the uterus and then stop, just keep going," Johnson notes.

The importance of creating these aggressive cells is that doing so has given the UNC researchers insight into triple negative breast cancer (TNBC), a highly recurrent tumor that spreads aggressively and carries a poor prognosis for patients afflicted with it.

Using a unique mouse model created in the Johnson lab, research assistant professor Dr. Amy N. Abell and graduate student Nicole Vincent Jordan helped showed that—similar to TNBC stem cells—normal tissue stem cells go through a similar program of molecular changes during organ development called epithelial mesenchymal transition (EMT). They say this suggests that breast cancer cells use a similar tissue stem cell molecular program for tumor metastasis, or cancer spread.

They discovered in their work that inactivation of the proteins MAP3K4 and CBP in trophoblast stem cells causes them to become hyperinvasive.

"Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT)," the authors write in the Cell Stem Cell paper. "Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties."

But more than that, the team also discovered—in collaboration with Drs. Aleix Prat and Charles Perou in the UNC Lineberger Comprehensive Cancer Center—that there is an overlap between the gene expression signature of the mutant tissue stem cell properties during EMT and the human TNBC gene signature that is predictive of invasiveness. Specifically, they found that the same genes were downregulated.

As the authors write: "The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer."

Translating that into something more layman-oriented, Johnson says, "This significant genetic intersection between tissue stem cells and TNBC has identified previously unrecognized genes that likely contribute to breast cancer metastasis. This newly identified gene signature is currently being investigated in different models of breast cancer with the goal of developing new therapeutic interventions for the treatment of TNBC."

Other UNC co-authors who contributed to the paper, "MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells," were Alicia A. Midland, Nancy L. Johnson, Deborah A. Granger, Piotr A. Mieczkowski and Shawn M. Gomez. Co-authors at the National Institute of Environmental Health Sciences were Weichung Huang and Leiping Li. The research was supported in part by the National Institute of General Medical Sciences, a component of the National Institutes of Health.