Unraveling the mechanics of cancer’s molecular engines

For more than a decade, Gregory Rogers, PhD, and his team have been at the forefront of unraveling the inner workings of cell division, specifically through centrioles—key structural components within the cell’s centrosome, which are crucial for cell replication. 

Rogers, who is a professor of cellular and molecular medicine at the University of Arizona College of Medicine and a member of the University of Arizona Comprehensive Cancer Center, is expanding and deepening this critical research through a five-year, $3.3 million grant from the National Institutes of Health, National Institute of General Medical Sciences called the R35 Maximizing Investigators’ Research Award. 

This work is a renewal of a previous award that continues the research he and his team began with their initial funding in 2020 during the COVID-19 pandemic. Through this new grant, the researchers will explore how centrioles are built and maintained in cells, how they duplicate and elongate and how, when dysregulated, they contribute to cancer. 

“Cancer is a disease of our DNA,” Rogers said. “In cancer cells, chromosomes, which are made of DNA, constantly change, and that fuels cancer initiation, growth, survival and malignancy.” 

When centrioles are overproduced, this disrupts the architecture of dividing cells and chromosomes change in their number and structure. 

“By uncovering how centrioles assemble and how their numbers are controlled, we can begin to understand what goes wrong in cancer and potentially how to intervene,” he said. 

Discovering how a cell works 

Centrosomes have a critical job within a cell. Made up of a pair of barrel-shaped centrioles, cells normally contain one centrosome that duplicates at the same time as our chromosomes.  

Afterward, cells enter mitosis with two centrosomes, and they organize the mitotic spindle into a bipolar football shape during cell division, ensuring that a single set of the duplicated chromosomes segregate accurately into the new daughter cells.  Although cells should have only two centrosomes before entering mitosis, in cancer cells, errors frequently occur in the centrosome duplication process and, as a result, they contain too many or too few. 

That error causes mitotic spindles to form irregular shapes, which then causes chromosomes to missegregate. Consequently, daughter cells receive an abnormal number of chromosomes. This constant scrambling of the genome is called chromosomal instability and creates new cellular entities, eventually giving rise to a cancer cell. 

“Our long-term goal is to understand how centriole number and size are regulated at the molecular level,” Rogers said. 

Errors in this process can lead to a cell developing more than two centrosomes, called centrosome amplification, a newly emerging hallmark of cancer cells as well as a driver of chromosomal instability and tumor progression. 

Over the past decade, the lab’s discoveries—such as the role of autophosphorylation, ubiquitination, and autoinhibition in Polo-like kinase 4 (Plk4) regulation—have helped them to develop a framework for discovering how cells normally duplicate centrosomes and prevent centrosome amplification. 

This template defines the structure, regulation, and activity of Plk4, an enzyme called a kinase. Plk4 is the master regulator of centriole duplication. If Plk4’s activity is unchecked, as can occur in cancer cells, then its hyperactivity triggers rampant centrosome amplification. 

Developing the latest technology 

The Rogers Lab uses advanced techniques, including CRISPR genome editing and expansion microscopy, that they developed during the first MIRA award period. The lab made critical technological advances that now form the foundation of their ongoing work by using the fruit fly Drosophila melanogaster. This next phase of the MIRA award enables his lab to make further discoveries that may one day assist in developing new therapeutic strategies for centrosome-related diseases. 

Under this renewed funding, Rogers and his team aim to examine how a cellular organelle (specifically, the centrosome) assemble and duplicate—which falls under a subfield of cell biology called organelle biogenesis.

They are asking, “What are the rules that cells use to ensure that a single centrosome duplicates only once per cell cycle?” 

This is important because cancer cells often do not obey these rules. 

“Our goal is to translate our understanding of centrosome assembly in the fly to positively impact human disease, specifically cancer, and this is applicable to almost all cancers because chromosomal instability is a hallmark of cancer cells,” Rogers said. 

Collaborating with cancer center members 

Rogers' contributions extend far beyond the lab. As associate head of faculty development in his department, he plays a vital role in mentoring junior faculty, overseeing career development, and supporting the department’s recruitment and retention. 

He is committed to graduate and postdoctoral training, having mentored more than 20 postdoctoral, doctoral and master's students, almost all of whom have gone on to successful careers in academia, industry and government. 

"Training students is hands down the most important and rewarding aspects of the job," Rogers said. "You get to enjoy having real positive impact on their future and take pride in watching a young trainee grow into mature scientist. It’s a commitment that I take seriously —and it’s worth it."

Beyond basic science, Rogers' research has significant implications for translational cancer biology. In collaboration with cancer center members, he is continuing his cell examination with Anne Cress, PhD, vice dean of operation and strategy for the University of Arizona College of Medicine and professor of cellular and molecular medicine and radiation oncology, Noel Warfel, PhD, associate professor of cellular and molecular medicine and shared resource co-director of the U of A Comprehensive Cancer Center experimental mouse. 

The researchers received a multi-principal investigator R01 grant from the National Cancer Institute Provocative Questions Initiative to investigate centrosome disappearance during early prostate tumorigenesis. Through the grant, they are exploring the oncogenic potential of centrosome loss in prostate cancer using human organoid models and tissue samples. 

“To me, this is another fun aspect of the job, being able to team up with my colleagues and work together on a common problem,” Rogers said. “It’s definitely an advantage to collaborate with other faculty members and their labs, to pool resources and share ideas. When we experience failures or setbacks, then we have colleagues to commiserate and form new strategies. And, when we have success, which is not often in science, then celebrations are much more precious and fun, too.” 

Rogers’ work is supported by the National Institute of General Medical Sciences of the National Institutes of Health, award number R35GM136265.