The role of asymmetric cell division in cancer is still a mystery. Institute fellow Raji Natarajan seeks to put a key molecular piece of information into the puzzle.
The most common malignancy diagnosed in children is acute lymphoblastic leukemia (ALL), which has a peak incidence in children ages two through five. The development of ALL can begin with a change to a single cell in the bone marrow. But what causes that change and how does that change ultimately lead to cancer?
Around the globe, hundreds of medical researchers are working to define the molecular mechanisms that control cell behavior, each hoping to add the critical bit of knowledge that will complete the puzzle and open the way to better treatments, cures and ultimately preventions.
Children’s Discovery Institute Fellow Rajalxmi Natarajan, PhD, is contributing to the effort by studying asymmetric cell division – the process by which a cell divides to give rise to daughter cells that exhibit distinct developmental destinies from their time of birth.
“Asymmetric cell division is important in embryonic development,” says Natarajan. “It’s what generates cell-type diversity in all multi-cellular animals.”
Stem cells are the most notable cells that can divide asymmetrically. They are also the most flexible. For starters, they can divide to produce a copy of themselves along with a second daughter cell programmed to differentiate into another type of cell altogether. Stem cells can also divide symmetrically to produce two new stem cells, or even divide into two differentiating daughter cells.
Normally, the process of stem cell division is under stringent control. If the control process is broken, however, stem cells may produce only more stem cells when they divide--a situation that has led to tumor development in some model organisms used for study.
The lowly fruit fly, Drosophila melanogaster, has provided scientists, including Natarajan, with a lot of the knowledge that has been accumulated about asymmetric cell division. “Many parallels exist between the molecules and mechanisms that control asymmetric divisions in flies, mice and man,” said Natarajan. “So there is good reason to believe that understanding the genes that control this basic process in the fruit fly will yield significant insight into human genetic control mechanisms.”
Specifically, Natarajan is looking into the interactions of three key genetic players in asymmetric cell division called Numb, Notch, and a relative newcomer, Sanpodo.
The Numb gene, which expresses a protein found in the cell cytoplasm (the gelatinous substance that fills most cells), and the Notch pathway, a signaling pathway involved in communication between cells, appear to control asymmetric divisions in mice and humans in essentially the same way they control asymmetric division in fruit flies. Mutations in Notch and Numb have been implicated in tumor development, and specific mutations in genes
R. Natarajan and J. Skeath
affecting the Notch pathway have been demonstrated to promote the development of T-cell acute lymphoblastic leukemia (T-ALL).
Natarajan is focusing her research on the third player mentioned above, Sanpodo. Sanpodo is a protein that was identified as a key link in the asymmetric division process by Natarajan’s mentor Dr. James Skeath. Skeath is an associate professor in the Department of Genetics at Washington University, and oversees Natarajan’s research.
“Sanpodo could be the real power player in the asymmetric cell division process -- promoting Notch activity in one daughter cell, and enabling Numb to block Notch signaling in the other so that each daughter cell acquires a distinct fate,” says Skeath.
But how dos Sanpodo do its job? Figuring that out is what excites Natarajan. She has set out to identify all of the proteins that interact with Sanpodo to understand precisely how Numb, Notch and Sanpodo interface. After scanning most of the fruit fly genome for genes that function with Numb and Sanpodo, she has narrowed her focus to five genes – several of which have known links to cancer.
“In order to fix a broken machine, you must first identify all of its component parts and figure out how they work under normal conditions,” said Natarajan. “That’s essentially what we are doing in the lab with this work – putting more pieces of the puzzle in place about basic cellular processes.”
The Children’s Discovery Institute believes that tomorrow’s cures and preventions will only arise from a solid foundation of understanding basic processes in cancer biology. The contributions of Drs. Natarajan and Skeath are key elements in building that foundation.
Dr. Natarajan, who is from Mumbai, India, earned her PhD in Cell Biology from Carnegie Mellon University in 2005 before coming to Washington University to join the Skeath lab. She received her Children’s Discovery Institute fellowship grant in 2007.