Alexander Yu. Nikitin, Biomedical Sciences, has a theory about why there’s been scant research on epithelial ovarian cancer (EOC): there are not enough survivors to advocate for it. EOC, the fifth leading cause of death in women, is otherwise known as the “silent killer,” as most women don’t have symptoms until it’s too late—seven or eight women out of 10 die from the disease within five years of diagnosis.
When Nikitin, who studies the link between stem cells and cancer, looked for research on stem cells in the female reproductive system, he didn’t find much. “People started to appreciate relatively recently that stem cells are involved in cancer,” Nikitin says. “When we decided to focus on ovarian cancer, we found that we don’t even have the knowledge about normal stem cells in the female reproductive system.”
A dearth of information is, of course, a boon for a researcher—and Nikitin’s lab has been working to understand the mechanisms of healthy stem cells in the female reproductive system and other locations, and in turn, how those cells become cancerous.
First Things First: Stem Cell Biology
“Stem cells can self-renew, but they can also make differentiated progeny, so the mechanisms which define these processes, or cell fate decisions, are very often affected during the formation of cancer,” Nikitin says. “But my philosophy is that you cannot understand the complexity or mechanisms of cancer at a global level unless you understand the mechanisms of normal development and regeneration.”
In the female reproductive system, for instance, Nikitin and his team want to understand whether the two main types of tubal epithelium cells in the fallopian tubes—ciliated cells and secretory cells—differentiate from the same stem cell type or if they each have their own. “If it is different stem cells and each of them cancer-prone, you’re basically dealing not with one ovarian cancer but two,” says Nikitin.
Even the assumed location of origin for EOC has been called into question in Nikitin’s investigations. “They’re called ovarian cancers, but probably about half of them develop first in the fallopian tube and then implant in the ovary because of the nice nutritional conditions,” Nikitin says. “But if you ask where the stem cells are in the fallopian tube, nobody knows for sure.
“We want to establish this hierarchy,” Nikitin continues. “How the cells are formed, where they come from, which are more susceptible to transformation, and why it is so.”
Pathologists have long known that some specific junctions in organs and tissues are more cancer-prone—the connection between two types of tissues in different organs, for instance. Because stem cell niches, or areas with a concentration of stem cells, have now also proved cancer-prone, Nikitin and his team are putting two and two together.
“My philosophy is that you cannot understand the complexity or mechanisms of cancer at a global level unless you understand the mechanisms of normal development and regeneration,” Nikitin says.
“We discovered a junction between ovarian surface epithelium and tubal epithelium, which is cancer-prone, and we’ve actually shown that it’s an area where stem cells are located. We’ve identified a previously unrecognized stem cell niche,” Nikitin says.
In addition to the junction between the ovary and fallopian tube, Nikitin and his team have also identified a stem cell niche between the esophagus and stomach, an area where instances of cancer are on the rise in both developed and undeveloped countries. Another project in Nikitin’s lab has been studying this niche and the conditions that lead to transformation.
Establishing the link between stem cell niches and these junctions is not only a major achievement but one which lays the groundwork for stem cell pathology—pathology directly related to changes in stem cells. With a $3 million grant from the Empire State Stem Cell Fund, Nikitin, in collaboration with John C. Schimenti, Biomedical Sciences, and Warren R. Zipfel, Biomedical Engineering, is working to develop better modeling and imaging of disease and to support more research on how and where stem cells transform.
“If you want to understand the mechanisms for development, you need to know where to look,” says Nikitin. “Many stem cells have anatomically defined stem cell niches where they reside. The idea is that if you know where they’re located, then the investigators can look there specifically and at an earlier stage. To my knowledge, so far, we’re the only place trying to use stem cell pathology to do this.”
Research Methods, an Evolution
The research methods Nikitin’s lab uses have evolved significantly over the last 15 years. His first series of achievements at Cornell were the development of successful mouse models for studying cancers at various locations where it had been particularly difficult to produce relevant models—the ovarian surface epithelium and the prostate, especially.
In the case of EOC, Nikitin developed a method for altering genes in the absence of promoters that can normally be used to mark certain tissues for deletion of genes. Instead, Nikitin and his team locally administered an adenovirus expressing Cre-recombinase, an enzyme that could recognize particular places, or loxP sites, on the gene. Because the ovary of the mouse resides within the bursa, administration of adenovirus allowed inactivation of two key tumor suppressor genes, p53 and Rb, specifically in the ovaria surface epithelium. This resulted in a 97 percent rate of EOC in mice models, and the EOC had many characteristics of its human analog. Tissue-specific altering p53 and Rb also resulted in a mouse model for one of the most aggressive forms of prostate cancer, which exhibits neuroendocrine differentiation.
The mouse models are still relevant, but Nikitin’s lab has expanded their toolbox. “Because there’s one problem with using mouse models,” Nikitin says. “They are not humans.” Nikitin’s group has become more interested in comparative studies, looking at the behavior of disease in mouse models and comparing it to what happens in human cells after gene alterations, the latter of which has been made possible with CRISPR-Cas9 gene editing. Nikitin also uses organoids, organ-like structures created to replicate what happens in an organism. These new comparative approaches depend on collaborations with Laura Hedrick-Ellenson, Weill Medical College, and Andrew K. Godwin, University of Kansas Medical Center, among many others.
Cornell, Cancer Research, and the Nature of Progress
Cancer—the idea of it and the reality of it—terrifies. Cancer researchers would like to find a cure, but Nikitin warns that too much demand for a fast and furious solution is not the way scientific progress happens. “You cannot simply order people, or assign one million scientists, because it doesn’t work this way,” says Nikitin. “Science is like a single organism. You can’t say, ‘Let us develop on the head,’ because you need to have the body.”
The revolutionary breakthrough of the CRISPR-Cas9 gene editing method, for instance, was developed by researchers working with bacteria, Nikitin says, without intended implications for cancer research. “If they had been forced, they wouldn’t have known how to do it. Discoveries come from who knows what,” he says. “It’s really important to have talented people who are able to pick up those things at the right stage of their maturity so to speak. And then move to translation.”
Progress, in short, is haphazard and unpredictable. But it’s also a team effort, and Nikitin says that the scientific community at Cornell embodies this ethic. “Cornell is such a unique place,” he says. “You don’t always have this extremely high collegiality and collaboration. And it’s very diverse. I always tell people that if you cannot find collaborators here, there might be something wrong with you, because there are so many options.”
Part of this collaboration is with colleagues, but this community also includes students. “Any research career consists of what you accomplish in your science. The other ingredient is what you accomplish in terms of training the next generation,” Nikitin says. “Cornell is particularly worthy in this way because we have absolutely wonderful students. If you feel satisfaction with what you accomplish and who you teach, the difficulties of an academic career, especially early on, are worth it.”