A chance encounter five years ago at a summer symposium, a shared interest in genetics — and some fruit flies — pointed University of Colorado researchers toward a laboratory collaboration that yielded potentially significant advances in dealing with colorectal cancer.
The findings, published in the journal Cell Reports, suggest a possible new strategy for attacking tumors by targeting specific enzymes that help a protein, called HIF1A, enable tumor cells to adapt to low levels of oxygen. While HIF1A can’t be shut down by drugs, the two enzymes, called CDK8 and TIP60, can be medicated to inhibit tumor growth.
If results continue to hold true in further studies, they could have implications for the treatment not only of colon cancer, but other varieties as well.
“Potentially,” cautioned Joaquin Espinosa, co-leader of the molecular oncology program at CU’s Cancer Center and scientific director of the Linda Crnic Institute for Down Syndrome. “With many cancers you get great results in the lab, but in clinical settings either the drugs don’t work or the tumor evolves.
“When tumors learn how to instruct the body to produce new blood vessels, it’s bad news, because now the tumor can grow very large. Then it can get into the blood stream — and that’s bad news because cancers can travel to other places and establish metastasis. Metastasis is what kills people.”
The next step, underway, will be to test the approach on mice. But fruit flies sent the research in its current direction.
It began in 2011, when Espinosa and colleague Matthew Galbraith were teaching a three-week symposium on genetics in New York. Among the international students at the course was Joel Perez-Perri, who worked in a lab at the Instituto Leloir in Buenos Aires and presented findings on the relationship of TIP60 to HIF1A.
At the time, Espinosa and Galbraith worked with human colorectal cancer cells in petri dishes, focusing on the CDK8 enzyme. In Argentina, Perez-Perri — under mentor Pablo Wappner — worked with fruit flies, which were more readily available and easier to manipulate genetically. Their “point of contact,” Espinosa said, was that both efforts addressed enzymes important to the protein HIF1A — only from different angles.
“HIF is a master regulator of the adaptation to low oxygen,” Espinosa said. “We and others are trying to find the second-in-command. HIF must be employing other proteins in the cell to achieve all of this. We found CDK8 was a key co-factor for HIF. Joel found that TIP60 was also a co-factor.”
They published their initial findings in the journal Cell in 2013 and took their joint effort to the next level. “There was a possibility that what Joel found was only true in flies,” Espinosa said. “So we set up our collaboration.”
Espinosa, who was born and educated in Argentina, arranged for Perez-Perri to visit the Colorado lab — then at CU’s Boulder campus — for a few months to test his fruit fly findings on human cancer cells.
“I was extremely excited when he offered me to work in his lab for a few months in order to explore in human cells what we had found in flies,” Perez-Perri said via e-mail from Heidelberg, Germany, where he now works at the European Molecular Biology Laboratory. “I did feel surprise and also was grateful, as in Argentina we had some ideas that were difficult to address because of lack of equipment and expertise.”
In Boulder, their work progressed.
“He did great,” Espinosa recalled. “Simply put, in the few months in the lab he showed that his results in flies were true in human cancer cells — specifically colorectal cancer cells.”
The research took further steps forward through the efforts of graduate student Veronica Dengler and collaboration in the private sector through the Wisconsin-based Promega Corp., a biotech firm. From Boulder to Buenos Aires to Madison, the joint effort allowed the work to draw on diverse areas of expertise and expanded resources.
“It would be very difficult and very expensive for any one team to have the whole spectrum of technology and approaches,” Espinosa said. “That’s when collaboration becomes very powerful. By talking and coordinating and agreeing to share results, we can work remotely, or bring our expertise together.”
It’s a model that has become typical, he added, as most published papers now feature authors from multiple institutions. And it’s a lesson Perez-Perri took with him when his career steered him to Europe.
“I learned the power of synergy with people with different expertise and backgrounds,” Perez-Perri said. “Many things that I learned from Joaquin I daily apply on my research and certainly helped me to become a better scientist.”