Inside all cells is a powerhouse that provides most of the energy a cell needs to survive. In cancer cells, this power generator, the mitochondrion, utilizes some molecular pathways that ordinary cells don’t.
That may provide an Achilles heel to enable researchers to find a therapy to kill cancer cells—without destroying healthy ones.
Mark Pellegrino is trying to find cancer’s weak spot in its mitochondria. He was recruited to the University of Texas at Arlington from Memorial Sloan-Kettering Cancer Center in New York, with the help of a First-Time Tenure Track Award from CPRIT.
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Inside all cells is a powerhouse that provides most of the energy a cell needs to survive. In cancer cells, this power generator, the mitochondrion, utilizes some molecular pathways that ordinary cells don’t.
That may provide an Achilles heel to enable researchers to find a therapy to kill cancer cells—without destroying healthy ones.
Mark Pellegrino is trying to find cancer’s weak spot in its mitochondria. He was recruited to the University of Texas at Arlington from Memorial Sloan-Kettering Cancer Center in New York, with the help of a First-Time Tenure Track Award from CPRIT.
In cancer cells, mitochondria are typically under stress, and rely on a rescue line from the cell’s nucleus in order to function.
To learn more about how this mitochondrial rescue works, Pellegrino uses a model organism—a roundworm—that has mitochondria similar to those found in human cells.
Roundworms are tiny and reproduce quickly. They are also transparent, which means scientists can see inside the worms under a microscope. Pellegrino can alter the genes in the roundworm to try to find out which ones help rescue the mitochondria. He uses transgenic worms that turn bright, fluorescent green if the mitochondria are stressed out and the rescue pathway is active. If the mitochondria are functioning typically, the worms look normal.
In addition to finding out which genes are most important for turning on the mitochondrial rescue pathway, Pellegrino is also looking for chemicals that can shut it down.
“We’re basically exposing our transgenic worms to stressful conditions that should turn them green, and then screening hundreds of chemicals to see if any of them turn off that green,” he says. If the worms turn back to their normal color, then that’s a good sign that the mitochondrial rescue pathway is no longer active.
Shutting down the mitochondrial rescue pathway might be a new way to target and kill cancer cells. If Pellegrino finds anything promising, it can be tested against cancer cells grown in the lab.
“In cancer, the mitochondria are dysfunctional and rely on these protective pathways to survive.If you inhibit this pathway it stops their growth or even kills them,” he says. “The magic is, if you treat a healthy cell, it doesn’t use this pathway and therefore is not affected.”
Pellegrino is also trying to figure out how infectious bacteria shut down this mitochondrial rescue pathway. As many as 1/5 of all cancers are initially caused by bacterial infections, Pellegrino says. Bacteria provoke an immune response that’s controlled by the mitochondrial rescue pathway that his group is studying. Like a war of escalation, some bacteria have figured out how to shut down this mitochondrial pathway, disabling the cell’s ability to kill the invader.
“If we can understand how these bacteria are turning off this response, then this may give us some clues for what to target for potential cancer therapeutics,” he says.
Pellegrino received his undergraduate and master’s degrees from McGill University in Montreal, Canada, and his Ph.D. in developmental biology from the University of Melbourne, Australia. He was a postdoctoral fellow at the University of Zurich before coming to Sloan-Kettering as a research associate in 2010.
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