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Fighting Glioblastoma: New Insights from Brain Organoids

Research into brain organoids reveals new ways to tackle glioblastoma.

Jérémy Raguin, Thierry Kortulewski, Oriane Bergiers, Christine Granotier-Beckers, Laure Chatrousse, Alexandra Benchoua, Laurent R. Gauthier, François D. Boussin, Marc-André Mouthon

― 5 min read


New Hope Against New Hope Against Glioblastoma change glioblastoma treatment. Innovative organoid research could
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Glioblastoma, often referred to as GBM, is one of the most aggressive types of brain tumors. It forms from glial cells, which support and protect nerve cells. Despite various treatments like surgery, radiation, and chemotherapy, GBM remains a tough opponent, often leading to poor outcomes for those diagnosed. This nasty tumor is known for its resistance to treatments and ability to invade healthy brain tissue.

Glioma Stem Cells: The Sneaky Culprits

Within the GBM are special cells called glioma stem cells (GSCs). These cells have unique properties that help them survive treatment and cause the tumor to come back. Think of them as the supervillains of the tumor world-hard to catch and always plotting their next move.

The Role of the Tumor Microenvironment

The environment around the tumor, known as the tumor microenvironment, also plays a significant role in GBM's resilience. This includes Blood Vessels and immune cells that, instead of fighting the tumor, can sometimes lend it a helping hand. For example, certain immune cells, like Tumor-associated Macrophages (TAMs), are often found in large numbers within GBM. These cells usually protect the body but can be tricked into creating conditions that help the tumor grow instead.

How TAMs Contribute to Tumor Growth

TAMs are like the neighborhood watch who ends up helping the criminals instead. They produce substances that support tumor cell survival and proliferation, inadvertently assisting in the tumor's growth. Interestingly, the type of TAMs present can vary depending on the tumor’s genetic makeup. This can mean that some tumors might have more "friendly" immune cells, while others might have a more hostile crowd.

The Challenge of Treatment

All these factors-GSCs, TAMs, and changes in the tumor's environment-make treating GBM particularly challenging. While some treatments might work temporarily, they often fail to eliminate the tumor for good. Scientists are still figuring out the exact roles of these components in tumor development and recurrence, and they need better models to study this.

Enter the Brain Organoids!

Recently, researchers have developed models called human brain organoids. These small, simplified versions of the brain can help scientists learn more about brain biology and conditions like GBM. However, these models can be a bit like a fancy restaurant meal that looks great but lacks essential ingredients, as they often miss the critical elements of blood vessels and immune cells.

Enhancing Organoids with Blood Vessels and Immune Cells

To improve these organoids, scientists have been working on adding blood vessels and immune cells into the mix. This is a bit like adding the secret sauce to a burger-everything tastes better with it! By using a type of cell called hemogenic endothelial cells (HECs), researchers aim to create organoids that not only resemble the brain more closely but also reflect its complex environment.

The Method Behind the Madness

In one approach, researchers start by cultivating stem cells and then guiding them to develop into different types of cells, including HECs. By doing this, they can create brain organoids that have both blood vessels and immune cells, thus simulating a more realistic brain environment.

The Benefits of a Vascularized Brain Organoid Model

Having these enhanced organoids is crucial for studying how GBM grows and how it responds to treatments. By replicating the tumor microenvironment more accurately, researchers can glean valuable insights into how neurons, blood vessels, and immune cells interact. This information is vital for developing better therapies.

What Did the Researchers Find?

When scientists created these vascularized organoids, they saw that the inclusion of blood vessels and immune cells did not hinder the development of other brain cells. In fact, it seemed to help. These organoids contained a variety of cell types similar to those found in the human brain, which is a huge step in the right direction.

Testing New Treatments

Another exciting aspect of these organoids is their use in testing treatments. By adding glioma stem cells and observing how they behave in these organoids, researchers can test new therapies in a more realistic setting. This could help find more effective ways to combat GBM.

The Role of Radiation Therapy

Radiation is often used to treat GBM, but interestingly, it can sometimes make GSCs more aggressive. This means that while radiation aims to destroy the tumor, it can inadvertently help some of the tumor's sneakiest cells to thrive. Researchers are keen to understand this paradox in order to improve treatment strategies.

The Power of Immune Cells

As mentioned earlier, immune cells play a complex role in GBM. In the presence of GSCs, some immune cells can start behaving more like "friends" of the tumor rather than "enemies." Researchers aim to determine how these immune cells change in response to GSCs and how they can be manipulated to fight the tumor more effectively.

The Future of Research on GBM

The hope is that as researchers continue to develop and refine these brain organoid models, they will provide a wealth of information on GBM. This could lead to breakthroughs in understanding how to treat this aggressive cancer, ultimately improving outcomes for patients.

Conclusion: Why Should We Care?

Ultimately, the quest to understand and find better treatments for GBM is about more than just science; it’s about people. Each discovery in the lab can spark hope for those affected by this challenging disease. By learning more about how GBM operates, researchers can help create new therapies that make a real difference in the lives of patients. And who knows? One day, these tiny organoids might just lead to the cure that brings an end to this cancer's reign of terror.

So here’s to science, perseverance, and the hope that we can outsmart glioblastoma!

Original Source

Title: Advanced human cerebral organoids as a model for investigating glioma stem cell interactions with microglia and vascular cells and response to radiotherapy

Abstract: The recent development of human brain organoids from induced pluripotent stem cells (IPSCs) enables the modeling of brain biology and pathophysiology, such as gliomas. However, most models lack vascular and/or immune systems, both of which play essential roles in maintaining brain health and in pathophysiological mechanisms. We have established a new method for generating vascularized complex cerebral organoids (CCOs) containing microglial cells (brain-resident macrophages) by incorporating bipotent hematopoietic/endothelial progenitors derived from the same IPSC lines during the early stages of development. This approach led to the formation of extensive vascular-like structures with blood-brain barrier characteristics, which were perfused upon transplantation into immunodeficient mice. Additionally, microglial cells exhibiting typical phenotypes and functionalities also developed within the CCOs. By coculturing CCOs with glioma stem cells, we demonstrated that this model effectively recapitulates the tumor niche of glioblastoma, showing vascular co-option, reprogramming of microglia into tumor-associated macrophages, and recurrence after radiotherapy. In conclusion, our vascularized and immunocompetent CCO model will be invaluable for understanding human brain development, exploring how this process is disrupted in diseases like gliomas, and discovering new therapeutic strategies.

Authors: Jérémy Raguin, Thierry Kortulewski, Oriane Bergiers, Christine Granotier-Beckers, Laure Chatrousse, Alexandra Benchoua, Laurent R. Gauthier, François D. Boussin, Marc-André Mouthon

Last Update: 2024-11-30 00:00:00

Language: English

Source URL: https://www.biorxiv.org/content/10.1101/2024.11.28.625826

Source PDF: https://www.biorxiv.org/content/10.1101/2024.11.28.625826.full.pdf

Licence: https://creativecommons.org/licenses/by/4.0/

Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.

Thank you to biorxiv for use of its open access interoperability.

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