For cancer cells to survive, grow and metastasize, they must continuously copy their DNA. Every time a cancer cell divides, it must duplicate the DNA in its chromosomes, passing one copy to each of two daughter cells. This process repeats, allowing tumors to multiply.
For decades, scientists have believed that a group of proteins known as the origin recognition complex, or ORC, was critical to that process. Scientists believed that these proteins, composed of six separate proteins in a complex, bound to chromosomes to help begin the DNA replication process.
Researchers in the lab of Anindya Dutta, Ph.D., chair of the Department of Genetics at the University of Alabama at Birmingham, are challenging that long-held theory through an R01 grant funded by the National Cancer Institute.
An unexpected lead
In his earlier research that began in 1994, Dutta identified many of the replication initiation proteins in human cells. About five years ago, Dutta’s lab discovered that, when three of the six ORC proteins are removed from cancer cells using modern genetic approaches, the cells remain viable and continue replicating their DNA. His current research is taking that discovery even further.
Dutta has been awarded a total of $11.4 million ranging more than 20 years. The current renewal will have UAB receiving $2.3 million over the course of five years, through 2031.
“The first questions the grant proposes to answer include ‘Are cancer cells devious?’ and ‘Have they discovered a new method to copy DNA without the protein that everyone thought was essential for the viability of cancer cells?’” Dutta said.
The earlier findings in Dutta’s lab related to ORC protein removal suggest that cancer cells may have evolved in unexpected ways to survive. “Cancers have acquired new properties allowing them to survive without the ORC.”
The discovery began with a question about DNA replication, but it led Dutta’s team into another area of cancer biology: gene regulation.
A replication protein with a different role
Chromosomes are long stretches of DNA where ORC normally binds to help initiate replication. But chromosomes also contain genes, segments of DNA that provide instructions for making proteins and controlling cellular functions.
Not every gene is active in every cell. A liver cell and a neuron, for example, contain the same DNA sequence but express different sets of genes. Cells control this process through epigenetic mechanisms, which determine which genes are turned on or turned off without changing the underlying DNA sequence.
Cancer cells rely heavily on these regulatory systems. They alter gene expression programs to support uncontrolled growth, survival and metastasis.
“We are very interested in studying what controls gene expression in cancer cells,” Dutta said.
This interest became central to the second part of the grant.
“The second part of what we are studying with this grant is the protein ORC, that we thought would be absolutely important in controlling copying of DNA, and how it was not found to be important for copying but instead was found to be important for controlling the regulation of gene expression,” he said.
The finding created a new scientific puzzle: If ORC is not required for DNA copying in these cancer cells, why does removing it change which genes are expressed?
Dutta has studied DNA replication and genome stability for more than three decades. His laboratory is internationally recognized for discoveries related to how human cells duplicate their DNA, including the identification of several ORC genes.
“I was studying ORC because my lab is very well known in DNA copying, and in fact my lab discovered many of the ORC genes,” Dutta said. “In the last cycle, we discovered two strange things: that cancer can survive without ORC and that cancer cells show changes in gene expression when ORC is removed.”
Searching for a cancer-specific bypass
Dutta says these findings come at a time when the field is beginning to reconsider assumptions about what cancer cells require to survive.
“Now the field is coming around to say maybe cancer can survive without these certain factors,” he said.
One of the major questions driving the research is whether cancer cells possess an alternative mechanism — an ORC bypass pathway — that allows them to continue copying their DNA. The answer could reshape scientists’ approach to the research of how cancer cells adapt and evolve.
Finding such a pathway would open additional avenues of investigation. Researchers could then determine whether the bypass mechanism exists only in cancer cells or it plays a role in normal biology as well. They could also examine whether the pathway depends on enzymes or other molecules that could eventually become therapeutic targets.
A collaborative environment for discovery
Dutta says the research environment at UAB has been an important factor in allowing complex, long-term projects like this one to move forward. While the questions his lab studies are complicated, he says the collaborative atmosphere makes the work possible.
“What is impressive about UAB is that the university is encouraging more and more investigators to stay in their research and not get discouraged quickly,” Dutta said. “UAB is an extremely positive atmosphere for research. We are good, and we can be even better if we continue on this positive path.”
Dutta described UAB as a place where researchers can continue developing ideas, even when experiments fail or funding is difficult. Persistence is essential in science, and failure is often part of the process. Only a small fraction of proposed grants receive funding, but Dutta says rejection can be part of improving research.
“Science is a matter of try and try again,” he said. “Science needs resilience and much more now than it did in the past.”
For Dutta, UAB is a growth atmosphere for all levels of research, from early investigators to senior scientists.
The potential impact on future research
As with many fundamental research projects, the long-term implications of Dutta’s research are significant. If researchers identify an ORC bypass pathway, they could gain new insight into how cancer cells maintain growth despite losing a biological system previously thought to be essential.
For Dutta, the ideal outcome is the discovery of a fundamental biological mechanism that scientists have overlooked. And though the clinical implications may still be years away, the discoveries made today will lay the foundation for tomorrow’s advances in cancer treatment.
This work is supported by a National Institutes of Health/National Cancer Institute R01 grant, a competitive funding mechanism that supports investigator-driven research into fundamental questions in cancer biology.