Brain Tumor & Microenvironment Research Group

Glioblastomas are highly malignant and invasive primary brain tumors that maintain close communication with their microenvironment. In our research group, we investigate the mechanisms through which tumor cells interact with each other and their surrounding microenvironment. Our findings have demonstrated that mitochondria can be transferred from normal astrocytes to tumor cells, promoting tumor growth and enhancing oxidative metabolism:

GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity (external link)

Stopping a tumor's 'cellular looting' may help treatment for brain cancers (external link)

Basic Researchers Discover Possible Target for Treating Brain Cancer (external link)

Mitochondria transfer occurs through cytoplasmic extensions known as microtubes (MTs), which form connections between tumor cells and also link normal astrocytes to tumor cells, creating an extensive communication network. Our current research focuses on unraveling the molecular mechanisms underlying this network and its role in driving treatment resistance.

Another key focus of our group is the immune microenvironment, specifically examining how cancer cell death influences immune responses within this environment.

Professor Hrvoje Miletic and his team at UiB have made groundbreaking discoveries that could provide new answers to what makes malignant brain tumors grow. The goal is to improve both survival and treatment of brain cancer.

By Paul André Sommerfeldt Published: 21.01.2025

The treatment for patients affected by serious brain tumors have more or less stood still for the past 20 years. This type of cancer is also difficult to treat due to the location of the tumor in the brain and the disease's resistance to traditional treatments such as radiation and chemotherapy. The average survival for this form of cancer is only 18 months.  

Physical connections discovered

Now, Professor Hrvoje Miletic and his colleagues at UiB, in collaboration with the Cleveland Clinic (external link) in the USA, have made discoveries that could potentially have great significance. In short, the discoveries show how cancer cells communicate with support cells in the brain (astrocytes (external link)).

Miletic has found, among other things, that there is a physical connection through a structure called "microtubes". 

– We have been able to show that this physical connection affects the energy supply and increases tumor growth. The cancer cells divide themselves in a high number, which leads to aggressive growth in the tumor, Miletic points out.

Specifically, it has been found that astrocytes transfer mitochondria to cancer cells, but exactly which mechanisms cause them to be physically connected through the microtubes is still unknown. We have an idea of ​​how this happens, and we would like to block this mechanism. Mainly because this affects the tumor's resistance to chemotherapy, Miletic explains.

Bildet viser overføring av mitokondrie fra astroytter til glioblastomceller. Mitokondriene i astrocyttene er rødfargete og tumorceller er grønne. Pilene peker på en microtube-forbindelse mellom en astrocytt og en tumorcelle som inneholder røde mitokondrier. Det ses også noen få mitokondrier i den grønne tumorcellen som har blitt overført.

May affect the immune-response

If the researchers are able to find out how to block these mechanisms, the "highways" into the tumor, this could also affect the immune response locally in the tumor. 

– Cancer cells suppress an immune response, but we first have to find out why this happens and how we can remove the blockade, says the professor.

In other words, the research is still exploratory, but the potential is great if the researchers were to "crack the code" when it comes to the mechanisms behind what causes tumor growth.

Miletic currently works as a consultant in neuropathology at Haukeland University Hospital and holds a 20% professorship at the Department of Biomedicine, UiB. His access to patient material is a strength for the research.

– It allows me to look at patient biopsies and use cell cultures from patient material for research, he explains.

• The research on mitochondria and energy in cells has previously been featured in National Geographic. Read the interesting story here: https://www.nationalgeographic.com/premium/article/mitochondria-tumor-cell-brain-cancer-treatment-glioblastoma  (external link)

New therapies 

In addition to improving survival, the researchers are hoping to develeop a form of gene therapy that will "disrupt" communication between cells and activate the immune response.

Gene therapy is a form of medical treatment in which genetic material is transferred to body cells or cancer cells, to correct a gene defect or, in the case of cancer, to either directly kill cancer cells, to block communication with the microenvironment or to make the body's own immune cells better at fighting disease. 

Such treatment requires that it's possible to find out which molecules can break the connections from cancer cells to the micro-environment.

Hvroje Miletic emphasizes the need to have a breakthrough in brain cancer research.

– Groundbreaking discoveries are needed to advance treatment. Much has already been tried in brain cancer, especially when it comes to targeted treatment, but no breakthrough has been achieved so far, says Miletic.

Links 

Stopping a tumor's 'cellular looting' may help treatment for brain cancers (external link)

UiB-forskere fant nettverk som forer hjernesvulster (external link)

Cellenettverk i hjernen fremmer aggressiv tumorvekst ved hjernekreft (external link)

Professor Hrvoje Miletic at the University of Bergen is part of the biggest research-environment on brain tumors in Norway. His work could be crucial for developing new and advanced treatment

• Hrvoje Miletic was born in Germany with Medical studies from Bonn, Hamburg and Vienna.
• He became a specialist in neuropathology in 2007, the same year he also defended his thesis in Cologne.
• He came to Bergen in 2007, first as a post-doc with a 20% position at Gade institute, from 2010 he has been a consultant at Haukeland hospital and professor at the Department of Biomedicine.
• Miletic is Principal Investigator at the Brain Tumor & Microenvironment Research Group.