Science has advanced one step closer towards figuring out how certain cancer cells work. Researchers at ETH Zurich demonstrated that skin cancer cells can transfer their mitochondria, the cell compartments that provide energy, to neighboring healthy connective tissue cells (fibroblasts) for the survival and growth of tumors. It leads to reprogramming of these healthy cells. Evidence shows that this transfer also plays a role in breast cancer and pancreatic cancer.
Previously, other research groups have shown that cells from the tumor’s environment can transfer their mitochondria to cancer cells, which enhances the fitness of the recipient cancer cells. To date, it was not known that the mitochondrial transfer also works in reverse, from skin cancer cells to healthy connective tissue cells. The study, led by cell biology professor Sabine Werner, was published on August 28 in the journal Nature Cancer.
The cancer cells use tiny tubes made of cell membrane material to transfer the mitochondria to healthy cells and connect the two cells — much like in a pneumatic tube system. The recipient fibroblasts are then functionally reprogrammed into tumor-associated fibroblasts, which mainly support cancer cells. Tumor-associated fibroblasts multiply faster than normal fibroblasts and produce more energy and growth substances, allowing the tumor to grow faster and become more aggressive.
It was already known that cells can exchange mitochondria via such connections. However, this mechanism is normally used for healing. For example, it has been shown that after a stroke, healthy nerve cells pass on their mitochondria to damaged cells in order to ensure their survival. Now, cancer cells were found to take advantage of this property to maneuver their own growth and functions.
“The cancer cells actually utilise a mechanism that is advantageous for injuries for their own purposes. This allows them to grow into a malignant tumour,” explained study leader Sabine Werner.
Last, but not least, the hijacked fibroblasts also alter the cell environment—the so-called extracellular matrix—by increasing the production of certain matrix components in such a way that cancer cells thrive. The extracellular matrix is vital for the mechanical stability of tissues and influences growth, wound healing, and intercellular communication.
It was actually a chance discovery, as Werner related. Her former postdoctoral researcher, Michael Cangkrama, discovered tiny tube-like connections between the two cell types in a Petri dish containing a co-culture of fibroblasts and skin cancer cells. He was then able to show that mitochondria from cancer cells are transferred into fibroblasts by way of these nano-connections.
In collaboration with other research groups at ETH Zurich, the researchers found evidence that this transfer also plays a role in other cancer types, such as breast cancer and pancreatic cancer. This is particularly important in the latter case because pancreatic tumours contain many fibroblasts, and their connective tissue is relatively large.
The cancer cells utilise the MIRO2 protein to transfer the mitochondria, the scientists reported. “This protein is produced in very high quantities in cancer cells that transfer their mitochondria,” said Werner.
According to the researchers, the new findings offer starting points for possible therapies. If this protein could be blocked, mitochondrial transfer would probably no longer work.
“The MIRO2 blockade worked in the test tube and in mouse models. Whether it also works in human tissue remains to be seen,” said Werner.
To find this out, the researchers first need to identify an inhibitor for MIRO2 that has few side effects in the human body. “If successful, such an inhibitor could be transferred to clinical applications in the longer term,” said Werner.
It is likely to be years, however, before such a therapy is developed and tested.
