Wistar Scientists Identify Therapeutic Target for Metastatic Cancers

Damaged “ghost” mitochondria are found to drive tumor progression.

Metastasis, or the spread of cancer from one place in the body to another, is responsible for more than 90% of all cancer deaths. Therefore, determining how and why this happens is an important part of cancer research. A new collaborative study led by scientists at The Wistar Institute identified one such mechanism thanks to “ghost” mitochondria.

Because they are the “powerhouse” of the cell, mitochondria (a specific organelle inside human cells) are crucial for cell survival, including tumor cells. However, recent research has shown that mitochondria in many human tumors lack an important protein called Mic60. Normally missing a crucial protein is a recipe for disaster, yet these mitochondria and their cells survive.

To determine how this is possible and how it affects tumor cell behavior, Dario C. Altieri, M.D., Wistar president and CEO, director of The Wistar Institute Cancer Center, and the Robert & Penny Fox Distinguished Professor, led a team of researchers in reproducing these types of low-Mic60 tumor cells in mice to enable closer examination. In doing so, they found two things. First, in cells where Mic60 was depleted, all of the mitochondria’s structures and functions were damaged or inhibited.

“They really didn’t produce any energy, which is what mitochondria do,” said Altieri. “That was the idea of calling them ‘ghosts’—because in essence the mitochondria were still there, but they didn’t do anything, or anything good, at least.”

Second, the scientists found that while inferior organelles are usually removed from healthy cells via a quality control process, the ghost mitochondria were not removed from tumor cells. Not only were they not removed, but they helped the cell metastasize.

Given these findings, the scientists speculate that the low-Mic60 tumor cells activate two pathways to stay alive: Akt (related to survival) and GCN2 (related to stress response). Drugs interfering with these pathways could, therefore, help to stop metastasis and kill the cancer.

“The idea would be to eliminate the adaptive responses that these Mic60-low tumors mount to remain alive and viable through a combination targeting of Akt and GCN2,” said Altieri.