Image Credit: Scientific Frontline
Scientific Frontline: Extended "At a Glance" Summary: CD47-Mediated Glioblastoma Progression
The Core Concept: Researchers have discovered that the protein CD47 plays a direct, internal role in driving the growth, movement, and invasion of glioblastoma cells into healthy brain tissue, operating independently of its previously established function in immune evasion.
Key Distinction/Mechanism: While CD47 was previously recognized solely as an extracellular "don't eat me" signal that helps cancer cells hide from the immune system, its newly identified mechanism is intracellular. CD47 sequesters a protein called ITCH, preventing it from breaking down another key protein, ROBO2. This shielding allows ROBO2 to accumulate and actively drive tumor progression and invasion.
Major Frameworks/Components:
- CD47: A protein found in high abundance at the invasive edges of glioblastoma tumors, directly correlating with poorer patient survival outcomes.
- ROBO2: A downstream partner protein shielded by CD47 that facilitates cancer cell proliferation, migration, and invasion.
- ITCH: A protein responsible for tagging ROBO2 for cellular degradation, whose function is inhibited when sequestered by CD47.
- CD47-ITCH-ROBO2 Pathway: The newly identified molecular chain of events acting as a central regulator of glioblastoma biology.
Branch of Science: Molecular Oncology, Cellular Biology, Neuro-oncology.
Future Application: The discovery establishes a foundation for novel, targeted clinical therapies designed to directly inhibit the CD47-ROBO2 pathway or disrupt the stabilization of ROBO2, offering new strategies to halt cancer spread beyond traditional immunotherapies.
Why It Matters: Glioblastoma is an exceptionally aggressive and lethal brain cancer, with standard treatments currently yielding a median survival of less than 18 months. Uncovering this non-immune mechanism provides critical new targets for therapeutic intervention, potentially improving survival rates by disabling the tumor's ability to invade healthy brain tissue.
Adelaide University researchers have uncovered a critical mechanism driving the growth and spread of glioblastoma – one of the most aggressive and lethal forms of brain cancer – potentially paving the way for more effective treatments.
In a new study led by scientists from the Centre for Cancer Biology (CCB), researchers identified a previously unrecognized role for a protein called CD47 in promoting tumor progression, independent of its known function in helping cancer evade the immune system.
Glioblastoma is extremely difficult to treat, with most patients surviving less than 18 months after diagnosis. Current treatments – including surgery, radiation and chemotherapy – offer only limited benefit, and the cancer almost always returns.
The new research, published today in PNAS, shows that CD47, already a target of experimental cancer immunotherapies, also plays a direct role inside tumor cells, helping them grow, move and invade surrounding brain tissue.
“We’ve known for some time that CD47 acts as a kind of ‘don’t eat me’ signal that helps cancer cells hide from the immune system,” said Dr Nirmal Robinson, senior author of the study.
“What we’ve discovered is that CD47 is doing much more than that; it’s actually driving the cancer’s ability to spread and grow.”
The team found that CD47 is particularly abundant at the invasive edges of glioblastoma tumors – the regions responsible for cancer spread into healthy brain tissue. Patients with higher levels of CD47 had significantly poorer survival outcomes.
In collaboration with Professor Stuart Pitson’s CCB team, researchers used a combination of laboratory experiments and animal models to show that removing or blocking CD47 dramatically reduced tumor cell proliferation, migration and invasion.
Tumors lacking CD47 grew more slowly and, in some cases, survival time in models nearly doubled.
These effects occurred even in the absence of immune cells, confirming that CD47 has a powerful tumor-promoting role beyond immune evasion.
The team also identified a key partner protein called ROBO2, which acts downstream of CD47 and contributes to glioblastoma growth and spread.
The researchers discovered that CD47 protects ROBO2 from being broken down inside the cell. It does this by sequestering a protein called ITCH, which would otherwise tag ROBO2 for destruction.
“Essentially, CD47 is shielding ROBO2, allowing it to accumulate and drive tumor progression,” according to Dr Ruhi Polara, who led the research alongside Dr Robinson.
“When we remove CD47, ROBO2 is degraded, and the cancer cells lose their ability to grow and invade effectively,” Dr Polara said.
The findings reveal a previously unknown molecular pathway – CD47-ITCH-ROBO2 – that controls how glioblastoma cells behave. This opens new possibilities for treatment strategies that go beyond current approaches.
While therapies targeting CD47 are already being tested in clinical trials for other cancers, they have shown limited success in glioblastoma so far. The new research suggests that directly targeting the CD47-ROBO2 pathway, or disrupting the stabilization of ROBO2, could be a more effective strategy.
“By understanding this mechanism, we now have new targets to explore,” Dr Polara said. “This could lead to the development of therapies that specifically block the tumor's ability to spread, which is one of the biggest challenges in treating glioblastoma.”
The study also highlights the importance of looking beyond the immune system when developing cancer treatments.
“This work changes how we think about CD47,” Dr Robinson said. “It’s not just an immune checkpoint; it’s a central regulator of tumor biology in its own right.”
The researchers say further studies are needed to translate these findings into clinical treatments, but the discovery represents a significant step forward in the fight against one of the most devastating cancers.
Published in journal: Proceedings of the National Academy of Sciences
Authors: Ruhi Polara, Briony L. Gliddon, Raja Ganesan, Lorena T. Davies, John Toubia, Sakthi Lenin, Ghizal Siddiqui, Olivia Morris-Hanon, Melinda N. Tea, Paul A. B. Moretti, Dung A. Nguyen, Chung Hoow Kok, Chloe Shard, Alexander H. Staudacher, Michael P. Brown, Darren J. Creek, Guillermo A. Gomez, Daniel Thomas, Stuart M. Pitson, and Nirmal Robinson
Source/Credit: Adelaide University
Reference Number: ongy032426_01
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