Epigenetic determinants of normal and tumor stem cell biology
Stem cells have great promise to treat a variety of human diseases. This type of therapy, called regenerative medicine, helps repair diseased organs through the stem cells’ ability to grow new, healthy tissue. However, administering living cells to a patient is not without risks, the greatest of which is that the stem cells could produce a devastating side effect of cancer instead of or in addition to the healthy tissue growth. At this point, we can neither estimate nor reduce these risks because we simply do not understand why some stem cells are “good,” helping to grow new healthy tissue, while others are “bad,” driving the formation of tumors. The only way to eliminate the risk of cancer is to understand the difference between “good” and “bad” stem cells, which will pave the way to developing methods to remove the cancer causing ability of stem cells while leaving their regenerative function intact, the main goal of this proposal.
The difference between a normal and a tumor stem cell must reside in the way they are programmed. Tumor stem cells have many of the same attributes as normal stem cells, but they must also possess unique properties that lead them to cause cancer. What are these properties? Recent studies suggest a critical regulator of stem cells is a protein called Myc, which has dual and opposite roles in stem cell biology: 1) on its “bad” side, Myc is one of the most prevalent and devastating oncogenes, or cancer-causing genes, and is responsible for a staggering number of human cancer deaths; 2) on its “good” side, Myc is essential for normal organ growth that is regulated by controlling stem cell behavior. We hypothesize that a key attribute of tumor stem cells is that they have too much Myc. Studies in mice indicate that eliminating Myc from stem cells disrupts their function and impairs cellular proliferation, which slows organ growth. For example, mice with Myc-less neural stem cells have a failed brain growth called microcephaly. Because microcephaly is also observed in people with mutated Myc, our studies in mice are highly relevant to humans and regenerative medicine.
One particularly notable aspect about both Myc-less neural stem cells and those with excess Myc is that their DNA structure, also called chromatin, is profoundly altered, which suggests that Myc may control stem cell behavior by regulating their chromatin. In our proposed research, we will study the difference between the chromatin of normal and Myc-less neural stem cells as well as tumor stem cells with excess Myc. Unlike DNA mutations, changes in chromatin are inherently reversible, making them more attractive targets for drug therapy. Our long-term goal is to develop methods for removing the cancer-causing function of stem cells through altering their chromatin while leaving their normal tissue-growing ability intact, facilitating the production of safe and effective regenerative medicine therapies.
How do we treat patients with regenerative medicine without at the same time giving them cancer as a side effect? Our overall goal is address this question to improve the safety of regenerative medicine therapies by defining what drives stem cells to cause cancer. Our studies will provide the foundation for developing methods to remove the cancer-causing ability of stem cells while retaining their ability to mediate healthy tissue growth or repair. Enhancing the safety of regenerative medicine therapies would be of great benefit to the State of California both in terms of improving the lives of patients as well as enhancing the knowledge of the stem cell field. It will also further the development of regenerative medicine leading to a new, valuable biotechnology. California should be a leader in developing safe, effective regenerative medicine.