Scientists have identified two proteins involved in the invasion of glioblastoma, a type of tumor that affects some brain cells. Targeting the action of these proteins represents an avenue to tackle this form of cancer.
Brain tumors are among the most complex forms of cancer to treat. Glial cells, which support the activity of neurons in the brain, can give rise to a particularly aggressive form of cancer known as glioblastoma. Glioblastoma cells are capable of spreading through brain tissue, causing neurological symptoms that are ultimately fatal and making it difficult to develop an effective therapeutic strategy. In a recent study published in Nature Communications, an Institut Pasteur team identified two proteins that play an essential role in the migration of glioblastoma cells.
The scientists initially focused on the PTEN protein, previously known for its role as a "tumor suppressor"; in other words it normally acts to inhibit the emergence or survival of cancer cells. It is involved in controlling cell proliferation and in the mechanisms of apoptosis, or cell suicide. In many tumors, the gene associated with PTEN is mutated, resulting in loss of PTEN activity. In particular, PTEN is altered in 70% of glioblastomas. "We knew that tumor cells do not express PTEN, and that restoring PTEN expression blocks the migration of these cells. But we did not know whether the absence of PTEN was sufficient to cause cell migration", explains Sandrine Etienne-Manneville, Head of the Cell Polarity, Migration and Cancer Unit.
A second protein linking PTEN and migration
To elucidate the question, the scientists placed glial cells in vitro in a situation that reproduces an inflammatory reaction in the brain, for example in response to a lesion. In these conditions, the cells tend to migrate to deal with the inflammation. The scientists observed that the cells lacking the PTEN protein migrated more quickly, and that the absence of PTEN therefore had a clear impact on migration. But the scientists then identified a link between PTEN and another protein, AMPK, an important metabolic regulator in cells, which plays a role in cell growth. "The connection between these proteins was previously unknown. We discovered it somewhat by chance, when looking for possible PTEN targets. We demonstrated that PTEN suppression induces hyperactivation of AMPK", explains Sandrine Etienne-Manneville, "and that if we block AMPK activity, we block migration."
In glioblastomas that do not express the PTEN protein, inhibiting AMPK activity with pharmacological inhibitors can slow tumor cell invasion. This discovery therefore paves the way for the development of novel therapeutic strategies. It could lead to a treatment for the most common and aggressive primary cancer of the central nervous system, which is resistant to all treatments and claims nearly 225,000 lives worldwide each year.
This study is part of the Cancer Initiative of the Institut Pasteur's strategic plan for 2019-2023.
PTEN inhibits AMPK to control collective migration, Nature Communications, August 11 2022
Florent Peglion1,7, Lavinia Capuana1,2,7, Isabelle Perfettini1, Laurent Boucontet3, Ben Braithwaite1, Emma Colucci-Guyon3, Emie Quissac4, Karin Forsberg-Nilsson5, Flora Llense1, Sandrine Etienne-Manneville1
1 - Cell Polarity, Migration and Cancer Unit, Institut Pasteur, CNRS UMR3691, Université Paris Cité, Équipe Labellisée Ligue Contre le Cancer, F-75015 Paris, France
2 - Collège doctoral, Sorbonne Université, F-75005 Paris, France
3 - Macrophages and Development of Immunity Unit, Institut Pasteur, CNRS UMR3738, Paris, France
4 - Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC University Paris 04 UMR S1127, Institut du Cerveau, ICM, Paris, France
5 - Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden