Years ago, a postdoc in the Ruohola-Baker Lab wrote a paper describing a biological mechanism in fruit flies that protects stem cells from apoptosis – in other words, that prevents cell death. The author suggested a systematic drug screen for molecules that might subvert this protective mechanism and induce cell death.
Such a drug would be a powerful tool in the fight against cancer. Scientists have long known that cancer stem cells exposed to chemicals and radiation are able to enter quiescence, a reversible state of dormancy. Later, the cancer stem cells reawaken and proliferate. Tumors return and the patient relapses.
At the time, Filippo Artoni was an undergraduate student researcher in the Ruohola-Baker Lab. Artoni designed the framework for the drug screen. Two other undergraduate students, Marcel Wu, and Joyce Lee, joined him in the search for a silver bullet capable of killing cancer stem cells. That work led to a paper in Nature Communications, authored by Yalan Xing.
That was 2015.
It was around then that Debra del Castillo responded to an ad for undergraduate students to help with a drug screen. “I was going to back school,” says del Castillo, who earned a degree in electrical engineering before leaving the field for twenty years to raise children and care for ailing family members.
“When I joined the project, I learned the basics of a screen and immediately saw that what we were doing was a great opportunity for young people to be part of a real scientific investigation,” adds del Castillo. “I really think that should be a part of every undergraduate experience.”
In the end, del Castillo’s tenure as an official member of the lab was brief. She accepted a full-time position, which she still holds, as a Huntington Study Group Research Coordinator. Nonetheless, she remains connected to the Ruohola-Baker Lab as a volunteer.
Since playing a role in some of the initial drug screens, del Castillo has recruited more than 50 undergraduate students who have followed in her footsteps, each helping to move the research effort forward, while gaining valuable hands-on laboratory experience. Many would likely not have had access to the opportunity without del Castillo’s knack for finding talent, often in students from backgrounds that are traditionally under-represented in biomedical research.
“Debra is an angel,” says Hannele Ruohola-Baker, PhD a Professor of Biochemistry and Associate Director of the Institute for Stem Cell and Regenerative Medicine (ISCRM). “She works from the grassroots up. She supports science as a social endeavor. Part of that is providing opportunities for those who need them most.”
Julien Ishibashi has been in the Ruohola-Baker lab for more than four years. He was assigned to the fly team after approaching Ruohola-Baker following a biochemistry exam. Today he is a research assistant and lab manager. “I joined the lab in time for the secondary screens – one of the first experiments I had been involved in,” says Ishibashi, who is now applying to graduate school. “It was definitely a great learning experience, figuring how to dissect and stain and run screens.”
Ishibashi is now the lead author of a paper, published in the journal Cells, that details the three-phase molecule screen effort and identifies a druggable pathway that could be a target for future cancer treatments.
“We know that cancer stem cells are able to withstand chemotherapy and radiation and that this elusiveness is what often causes relapses,” says Ruohola-Baker. “Our goal was to study how normal adult stem cells enter quiescence so that we could better understand how to attack cancer cells.”
In the first two phases of the investigation, the researchers used fruit flies to screen drug candidates. In a third phase, the team screened promising drugs in breast cancer organoids grown from cancer stem cells. The experiments revealed a series of small molecules that seemed to induce apoptosis in cancer stem cells.
“There was definitely a eureka moment when we first found a drug that worked,” recalls del Castillo. “When we saw apoptosis, it was a very big deal.”
The researchers focused their attention of the NF-kB signaling pathway, which plays a role in the development and death of cells and contributes to the growth and metastasis of cancer cells. NF-kB signaling pathway turned out to be a druggable pathway in stem cells. “We saw in the fruit flies and the organoids that our molecules were killing cancer cells,” says a Riya Keshri, a postdoc in the Ruohola-Baker and one of the study’s authors. “We’re keeping our fingers crossed that this approach could help patients someday.”
In the meantime, the search for even more effective molecules continues. As the research moves forward, Ruohola-Baker hopes her lab can partner with experts at the Fred Hutchinson Cancer Center on in vivo modeling. In another collaboration, scientists at the Institute for Protein Design are developing synthetic proteins and nanocages that could be used to turn the drug into laser-guided missiles, targeting cancer stem cells, while sparing healthy stem cells, and protecting patients from the worst side effects of cancer treatment.
Through it all, Ruohola-Baker emphasizes the impact the undergraduate students have had on her lab and the potential they hold to reshape the face of biomedical research. “We believe under-representation in science is a problem that must, and can be solved. We can do our part by opening doors to our lab and supporting our students at each step so that we eventually have a more diverse field at the faculty level. That’s what’s most exciting to me.”
Funding: This research was funded by a gift from Hahn Family and partly by grants from the National Institutes of Health R01GM097372, R01GM083867, 1P01GM081619, U01HL099997; UO1HL099993 for HRB