Northwestern Medicine scientists have uncovered new details about the genetic structure of ovarian cancer stem cells, according to a study published in Advanced Science.
Inside cells, DNA mixes with proteins to form chromatin within the nucleus. Within chromatin, structures called packing domains form when chromatin fibers fold together. These chromatin packing domains are critical for regulating gene expression, DNA replication and preventing DNA damage.
While it’s well known that DNA processes are disrupted in cancer, less is understood about how cancer impacts the organization of chromatin, said Daniela Matei, MD, chief of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology, who was co-senior author of the study.
“Within cancer, there is a rare population of cancer stem cells that are able to renew themselves and also give rise to other cancer cell populations,” said Matei, who is also the Diana, Princess of Wales Professor of Cancer Research. “These cancer stem cells are considered to be the root of cancer. They are resistant to chemotherapy, and our question was: how are they different from other cancer cells?”
In the study, Matei, along with co-senior author Vadim Backman, PhD, the Sachs Family Professor of Biomedical Engineering and Medicine, utilized optical spectroscopic nanosensing technology to observe the DNA organization of cancer stem cells.
They found that ovarian cancer stem cells have increased numbers of chromatin packing domains, which enabled increased transcriptional plasticity, allowing the cancer cells to swiftly change gene expression in response to stressors such as chemotherapy.
Next, by employing advanced sequencing techniques to identify histone interactions with the cancer stem cell DNA, investigators found that several chromatin regions were differentially activated in stem cells versus non-stem cells. The ovarian cancer stem cells activated genes related to DNA repair.
The findings underscore the adaptability of ovarian cancer stem cells and may provide new potential targets for treating the cancer, Backman said.
“Cancer stem cells are masters at adapting to anti-cancer therapeutics. This is rooted in their cellular transcriptional memory, which in turn is encoded in chromatin geometry,” said Backman, who directs the Center for Physical Genomics and Engineering at Northwestern. “Our results show that it is feasible to use small molecules to reprogram this memory, prevent cancer cells from acquiring stemness properties, and thus help existing therapies kill tumors better.”
Lastly, investigators screened drugs which may be able to decrease the number of packing domains within cancer stem cell lines. They found that DNA methyltransferase inhibitors and other histone modifiers significantly reduced the number of packing domains in the cancer cells, making them easier to target with chemotherapy, Matei said.
“We used epigenetic drugs and show that they indeed reduced the packing domains,” Matei said. “When you treat cells with these drugs, the stem cells differentiate into non-stem cells. We can eradicate them in vitro and in vivo and make them more sensitive to chemotherapy, reversing that phenotype.”
Building on this discovery, Matei and Backman will work to identify additional compounds which could be useful in targeting chromatin packing domains in ovarian cancer.
“In addition to screening for drugs, the other big question is whether this a characteristic just of stem cells or if there are other treatment-resistant cells that have the same features,” Matei said.
Backman and Matei are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The study was supported by National Institutes of Health grants U54CA268084-02, T32GM142604, R01CA228272 and T32AI083216. Additional funding was provided by the National Science Foundation under grant EFMA-183096, the U.S. Department of Veterans Affairs under grant BX000792-09A2, the Ovarian Cancer Research Alliance postdoctoral fellowship, the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center, and philanthropic support from Rob and Kristin Goldman, Susan Brice, the Christina Carinato Charitable Foundation and David Sachs.
