We tend to think of evolution as an inevitable, but positive, force in nature and in biology. But as scientists have developed ever more precise mapping of the human genome, they’ve begun to realize that natural selection at the genetic level could be responsible for both the growth of cancer and its resistance to treatment as it helps sick cells survive and undermines remission.
This phenomenon is at the heart of a new research collaboration between Kevin Morris, Ph.D., a professor and associate director of the Center for Gene Therapy in the Hematologic Malignancies and Stem Cell Transplantation Institute at City of Hope, and Erez Y. Levanon, Ph.D., associate professor in the Faculty of Life Sciences at Bar-Ilan University in Israel. As investigators, both scientists are fascinated by how natural selection plays into the evolution of cancer and, in particular, by the effects of RNA editing at the molecular level.
Morris is an international leader in long noncoding RNA (lncRNA) biology, which he is working to manipulate as a way of controlling and/or repressing cancer, HIV-1, and other diseases such as cystic fibrosis. Levanon focuses his lab’s research on better delineating the extent of RNA editing in human and animal models, and he is an expert on an RNA-related enzyme called ADAR. Through a variety of methods, the pair hope to identify mutations in ADAR-edited lncRNAs and determine their role in cancer, which could make them valuable targets for killing cancer cells of all types.
Morris and Levanon’s collaboration is the result of a grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, which was established in 2016 by a generous gift from the Harvey L. Miller Family Foundation to support the exchange of ideas, strategies and therapies between City of Hope and Israeli investigators sponsored by the Israel Cancer Research Fund.
“The Barron program grant advances our research by creating alternative paradigms to operate in,” Morris said. “Erez has a problem that he needs to solve, and I can try to help him solve it. We come at it from different perspectives, and that allows for creativity. This gets back to Einstein, who said creativity is more important than knowledge. As I’ve aged in life and in science, I see that. What I’ve appreciated in working with Erez has been the creativity.”
In cancer, normal cells mutate and become uncontrollable. In the past, researchers looking to understand and restrain this process focused on studying DNA. But now that the human genome has been fully mapped, new tools have allowed scientists to discover that 98% of the genome is made up of noncoding RNAs sometimes referred to as “genomic dark matter” and that this network of modulating genes is shared between various cancer types.
“We were convinced as a community that it was just: DNA makes RNA, RNA makes protein, and that protein makes your fingernails and your hair and your eye color, and everything’s controlled that way,” Morris said. “Now we’re learning there’s a whole dark fabric underneath it.”
In their study, Morris and Levanon plan to explore the specific network of noncoding RNAs that actively modulate the genes that drive a cell to become cancerous. Relevant discoveries in this RNA-based network could lead to new mechanisms for killing specific cancer cells. The Barron grant is allowing them to accelerate this exploration of RNA editing by bringing their individual interests together in singular purpose.
“Fundamentally, I am very interested in evolution and natural selection, what component of noncoding RNAs drives that process and whether RNA itself can control the genome,” said Morris, who originally joined City of Hope in 2004 then pursued his research at Scripps Research Institute from 2005 to 2016 before rejoining City of Hope.
Chemotherapy is often effective. But when a patient goes into remission only to have the cancer reoccur years later, it could be because of the evolutionary capacity of these long noncoding RNAs (lncRNAs), which may play a role in helping one of the cancer cells to survive and propagate. Morris and Levanon are trying to uncover the mechanism in the genomic fabric that drives this oncogenesis (the process by which healthy cells become cancer cells) and the cancer’s resistance to drugs.
They hypothesize that an RNA-edited lncRNA pathway can be present across a variety of cancer types — lung, breast, prostate, pancreatic — and that this RNA editing drives the cancer’s progression and resistance. Using genome sequencing, they’re working to create a massive model that compiles every transcript in the cancer cells of all cancer types and establishes common themes. “There are commonalities between them,” Morris said, “and if we can find that root commonality, we’ll have a key we can turn to shut down the cancer.”
To test their theory, they plan to screen more than 10,000 patient samples to reveal the role of RNA editing within cancer-specific lncRNAs. They’re going to look at several cancer types and locate the lncRNAs that have been instilled through evolution and natural selection during cancer, as well as during cancer treatment. If they can identify the mutation hot spots in the lncRNAs that drive chemotherapy resistance, they can possibly target and inhibit that pathway so the drugs can do their work.
Cephalopods such as cuttlefish and octopuses use RNA editing to change proteins instantaneously to protect themselves from predators. It’s a process Morris likens to jetlag, during which pressure is placed on the human system to adapt to a new environment, likely through lncRNAs that adjust our circadian rhythms and signal us to change how we feel and behave. Similarly, the RNA-binding ADAR protein is an RNA editor, which means that it can encourage the RNA to form a different structure using other proteins that forges a new pathway to help the cancer cells survive.
“Cancer is evolution on hyperdrive,” said Morris. “It’s a great system to study natural selection because if you’ve got cancer, it’s a cell that’s gone rogue. When the immune system lets its guard down or is unable to control it, the cell finds a niche, evolves and creates a tumor microenvironment.”
It’s still unclear how this RNA editing works, but these lncRNAs could become much more precise targets for treatment since they are very specific to the pathways they regulate. Levanon has spent months doing deep sequencing analysis of a massive amount of data from patient samples, interrogating pathways to find the best ones for Morris’s lab to focus on. Together, they will develop a complex assessment of the role of ADAR activity on lncRNAs in human cancer. These investigations could then lead to the development of new therapeutics.
“What’s going to happen is scientists will start locating very refined targets,” Morris said. “Meaning, you hit five lncRNAs that completely control that pathway, and it may shut that entire cancer cell down because they’re unique to that cancer cell.”
Morris admits that the complexities in this new area of research, which require a shift in thinking away from established dogma, can spark confusion and resistance in the scientific community. But that challenge is part of what drives him.
“I like this kind of work because no one on the planet knows the answer — we’re probably the closest to figuring it out,” said Morris, who has been digging into lncRNAs since the turn of the millennium. “How things work mechanistically is very interesting to me. I want to understand the fabric of the cell. This dark matter is fascinating.”
Morris credits the Barron program with granting him the freedom to indulge his most forward-thinking scientific curiosities. “These funding resources allow for real breakthroughs to be supported,” Morris said. “You develop a creative idea, it’s peer reviewed and then you have a go at it. It’s seed money for creative collaborations, innovative thinking, outside-the-box approaches — and that’s where true discoveries come from.”