Researchers decipher a key mechanism that controls pancreatic cancer growth

A new understanding of how pancreatic cancer cells evade the body’s immune system has emerged from laboratory research, potentially shifting how scientists approach treatment. An international team has identified a key mechanism that allows these cancer cells to remain undetected, and blocking this mechanism dramatically reduced tumor size in animal models.

Unraveling the Role of MYC

The findings, published in Cell, are the result of work led by Martin Eilers, Chair of Biochemistry and Molecular Biology at the University of Würzburg (JMU), and carried out by Leonie Uhl, Amel Aziba, Sinah Löbbert, and collaborators from JMU, the Massachusetts Institute of Technology (USA), and Würzburg University Hospital. The project received funding from Cancer Research UK, the Children Cancer Free Foundation (Kika), the French National Cancer Institute (INCa), and an Advanced Grant from the European Research Council awarded to Martin Eilers.

The research centers on the oncoprotein MYC, described by Martin Eilers as “one of the central drivers of cell division and thus of uncontrolled tumor growth” in many types of tumors. Scientists have long sought to understand how tumors with high MYC activity avoid detection by the immune system, despite their rapid growth.

Did You Know? Cancer Grand Challenges, which partly funded this research, provides awards of up to £20m to international teams tackling the toughest challenges in cancer research.

MYC’s Dual Role in Cancer Cell Survival

The study reveals that MYC has a previously unrecognized function. When cells are under stress, such as within a rapidly growing tumor, MYC doesn’t just bind to DNA to promote growth. It also binds to newly formed RNA molecules. This binding causes MYC proteins to cluster together, forming “molecular condensates” that attract other proteins, including the exosome complex.

The exosome complex then breaks down RNA-DNA hybrids, which are considered cellular waste products. These hybrids normally trigger an alarm signal within the cell, alerting the immune system to a problem. By organizing the degradation of these hybrids, MYC effectively silences the alarm.

Camouflage and Immune Evasion

This process allows MYC to act as a camouflage mechanism, preventing the immune system from recognizing and attacking the tumor. Researchers determined that a specific RNA-binding region within the MYC protein is responsible for this camouflage, and importantly, this region is separate from the part of MYC that drives cell growth.

Experiments in animal models demonstrated the impact of disrupting this camouflage. Tumors with a genetically modified MYC protein, unable to block the alarm pathway, shrank by 94 percent within 28 days – but only in animals with intact immune systems. Normal MYC tumors, in contrast, increased in size 24-fold during the same period.

Expert Insight: The discovery of this dual function of MYC is significant because it identifies a specific target for potential therapies. Previous attempts to block MYC entirely have been hampered by its importance in healthy cells, but targeting only its RNA-binding function could offer a more precise approach.

Future Directions and Therapeutic Potential

The findings suggest that future cancer drugs could focus on inhibiting MYC’s ability to bind RNA, leaving its growth-promoting function intact while disrupting its immune-evading capabilities. However, Martin Eilers cautions that further research is needed to understand how RNA-DNA hybrids are transported out of the cell nucleus and how MYC’s RNA binding affects the tumor’s immediate environment.

Dr. David Scott, Director of Cancer Grand Challenges, noted that this research exemplifies how uncovering the mechanisms tumors use to hide from the immune system can open up new possibilities for treatment, potentially benefiting both adult and childhood cancers.

Frequently Asked Questions

What is the role of the MYC protein?

The MYC protein is a central driver of cell division and tumor growth. The study revealed it also has a second function: camouflaging cancer cells from the immune system by degrading alarm signals.

How does MYC hide tumors from the immune system?

MYC binds to RNA, forming clusters that attract the exosome complex. This complex breaks down RNA-DNA hybrids, which normally signal the immune system that something is wrong, effectively silencing the alarm.

What were the results of the animal model experiments?

Tumors with a defective MYC protein shrank by 94 percent in 28 days, but only in animals with intact immune systems. Tumors with normal MYC increased in size 24-fold during the same period.

Could a deeper understanding of MYC’s functions lead to more effective and targeted cancer therapies in the future?