How does cancer get out of the prostate and into someplace distant, like the liver? With lots of bending and stretching. To become extra flexible, prostate cancer cells re-activate a genetic process that was turned off in infancy. A Brady team, led by radiation oncologist Phuoc Tran, M.D., Ph.D., and Reem Malek, Ph.D., a postdoctoral fellow in Tran’s lab, has uncovered exactly how this works.
“TWIST1 is a cell plasticity factor that is used in embryonic development,” explains Tran. “Our group has found that it plays a critical role in promoting prostate cancer metastasis.” In previous studies, Brady scientist Paula Hurley, with Brian Simons, D.V.M., Ph.D., Ashley Ross, M.D., Ph.D., and Ted Schaeffer, M.D., Ph.D., found that TWIST1 turns on a gene called HOXA9. This was surprising: HOXA9 “has long been associated with some forms of leukemia, but has never been implicated in prostate cancer,” Hurley says. “We discovered that TWIST1 and HOXA9 are silenced shortly after birth.” In collaboration with University of Washington scientists led by Colm Morrissey, “we showed that TWIST1 and HOXA9 co-expression was re-activated in mouse and human primary prostate tumors, and further enriched in human metastasis.”
Think about old books buried deep in the stacks of a library, says Tran: “The information is there, but you can’t get to it.” Through a series of events at the molecular level, instigated by TWIST1, the information in HOXA9 makes its way to the library’s reading room.
“But it may be possible to stop this,” says Malek. In the laboratory, the team found that “targeting HOXA9 was sufficient to prevent TWIST1-induced aggressive prostate cancer,” which means that this program is “therapeutically targetable.” Hopkins investigators Steven An, Ph.D., and Ted DeWeese, M.D., Ph.D., also contributed to these findings. This work, published in Cancer Research, was funded by gifts from the Motta and Nesbitt families and grants from the Prostate Cancer Foundation, Movember Foundation, the National Institutes of Health and the Department of Defense.