Dr Sergey Malchenko | The Mystery of Mitochondrial Transfer: Understanding Brain Tumour Development

Understanding how brain tumours grow is vital to the development of novel approaches to beat this type of cancer. In ground-breaking research, Dr Sergey Malchenko from the University of Illinois College of Medicine Peoria, USA, has identified a cell communication phenomenon called mitochondrial transfer between particular types of brain cells. Alongside colleagues, he works to understand this process, allowing him to decipher its impact on the development of brain cancer.

Neural Stem Cells and Astrocytes

The central nervous system consists of the brain and spinal cord. However, these are not just made up of nerve cells, as the name implies. While there are plenty of nerve cells (also known as neurons) that are vital for the communication and coordination of the body through the conduction of electrical impulses, there is a myriad of other types of cells called glia. Glia cells carry out critical functions throughout the nervous system, supporting the nerve cells in a wide variety of ways.

Dr Sergey Malchenko conducts research at the University of Illinois College of Medicine Peoria, USA. He explains that astrocytes are one of the most abundant types of glial cells in the central nervous system, which help to regulate the environment of the nerve cells. He adds that there are also neural stem cells in the brain, which have a role in the regeneration, repair, and development of the nervous system, with the potential to grow into new neurons, as well as other types of brain cells. Deciphering the communication – cell signalling – between neural stem cells and the astrocytes in the surrounding area would likely help us understand how brain tumours develop.

Communication Using Mitochondria

Mitochondria are organelles, structures found within cells which have a particular role. They are most commonly known for being the ‘powerhouse’ of the cell – the site of cellular respiration where energy is released. They also play a vital role in cell communications. In the process called mitochondrial retrograde signalling, the mitochondria release specific molecules within the cell, which then act on the nucleus, influencing the expression of certain genes.

New developments in the world of mitochondria and cell signalling are shedding further light on these vital processes. Another communication phenomenon called intercellular mitochondrial transfer (iMT) has recently been described across different types of cells. This unique communication system uses tunnelling nanotubes (TNT), the formation of tiny hollow structures, for targeted transfer of mitochondria between cells.

Dr Malchenko’s research has led to the first evidence of iMT occurring in particular types of brain cells. His recent research has confirmed iMT between neural stem cells and astrocytes, but most significantly, demonstrated that iMT occurs between brain cancer stem cells (CSCs) and astrocytes.

S Malchenko, et al., Characterization of brain tumor initiating cells isolated from an animal model of CNS primitive neuroectodermal tumors, Oncotarget, 2018, 9(17), 3733-3747.

Understanding Brain Cancer Stem Cells

CSCs have similar characteristics to stem cells in that they can self-renew and change into other types of cells. Their presence is linked to the relapse and spreading of cancer with the formation of new tumours, and researchers are increasingly interested in CSC iMT and, in particular, how this communication influences neighbouring cells.

Dr Malchenko notes that CSC mitochondria signalling can promote many factors that make the cancer worse, including increased self-renewal, growth and tumour metastasis (spreading to other areas of the body), resistance to drug treatment, and alterations in metabolic plasticity (the ability of cells to adjust their metabolism in response to changes in their environment).

The role of the iMT in the initiation and progression of different types of cancer is not fully understood, and being able to target these problematic CSCs and their communication pathways could offer a novel approach to fighting cancer. In particular, the impact of mitochondrial transfer in the human nervous system and its role in brain cancer largely remains a mystery – but one that Dr Malchenko is determined to solve.

Mitochondrial Transfer Between Brain Cells

Dr Malchenko and his colleagues carried out a series of co-culture experiments using a variety of combinations of cells to investigate iMT. They looked at human neural stem cells and brain CSCs, which are also known as brain tumour-initiating cells (BTICs), and their mitochondrial signalling with close-by astrocytes. The team found evidence of iMT from both human neural stem cells and from BTICs to astrocytes, with some interesting differences which warrant further exploration.

Dr Malchenko explains that mitochondria transferred to astrocytes, from both neural stem cells and BTICs, triggered similar transcriptome changes in the receiving astrocytes. Such changes relate to the regulation of certain genes, which in turn result in various changes within the cells, depending on which genes are turned on or off. The team found that in contrast to the neural stem cells, the mitochondria transferred from the BTICs had a significant proliferative effect on the astrocytes, causing them to increase in numbers rapidly. They also suspect that the effect of iMT on the transcriptome changes and, in turn, the growth and proliferation of the astrocytes is due to mitochondrial retrograde signalling between the transplanted BTIC mitochondria and the receiving astrocyte nuclei.

Future Brain Cancer Research

The team’s previous research enabled the development of a method to produce human radial (RG) cells – precursors to neural stem cells – using induced pluripotent stem cell (iPSC) technology. They also established an animal model of brain cancer to allow the study of the disease. Dr Malchenko explains that these methods allow large quantities of RG cells and BTICS to be produced, enabling different types of experiments to be conducted. He adds that they were also able to use the RG cells to produce astrocytes at various stages of development, and highlights that their reproducible cell production methods and animal models could be used to further study the molecular impact of iMT and mitochondrial signalling within and between brain cells.

Dr Malchenko’s recent work forms a basis for understanding the impact of iMT on the mitochondria receiving astrocytes, providing new insights into the mechanisms of mitochondrial retrograde signalling pathways. Deciphering the impact of this communication between brain cells and having a reliable and reproducible in vitro model to allow further study of these cell interactions opens exciting new doors in the quest to uncover novel targets for cancer treatment.