Pancreatic ductal adenocarcinoma, one of the most aggressive forms of cancer, is often described as “immunologically cold” due to its limited ability to provoke an immune response. For years, the MYC protein has been recognized as a key driver of tumor growth, but the mechanisms by which these rapidly developing tumors evade detection by the body’s immune system remained unclear.
Now, an international research team led by scientists at the University of Würzburg, in collaboration with researchers at MIT and Würzburg University Hospital, has identified what they describe as a molecular “invisibility switch.” Published in the journal Cell on , the study reveals that MYC can transition from its well-established role in regulating DNA to a separate function that actively suppresses the body’s innate immune signaling pathways.
MYC’s Shift from DNA to RNA Under Cellular Stress
MYC is well-known for its role in promoting uncontrolled cell division. It typically functions by forming a complex with MAX and binding to specific regions of the genome, thereby altering gene expression within tumor cells. However, this new research demonstrates that MYC doesn’t always remain anchored to DNA.
The authors found that when cellular transcription is disrupted and RNA accumulates within the cell, MYC relocates from DNA to nascent RNA. In this new location, MYC forms dense molecular clusters around double-stranded RNA and structures called R-loops, which are hybrids of RNA and DNA. This shift in location is crucial to understanding how MYC helps cancer cells evade the immune system.
The study identified four RNA-binding regions within the MYC protein, labeled RBR I through RBR IV. RBRIII proved to be particularly important. It promotes the formation of MYC clusters and facilitates the recruitment of the nuclear exosome, a complex responsible for degrading RNA, to areas where abnormal RNA structures accumulate. Importantly, this RNA-binding function operates independently of MYC’s traditional role in activating gene transcription.
Silencing Immune Alarms Before They Sound
Normally, RNA-DNA hybrids formed by R-loops can activate the body’s innate immune defenses. These hybrids are recognized by the pattern recognition receptor TLR3, which then activates the kinase TBK1, initiating a cascade of immune signaling events.
The researchers discovered that MYC, through its RBRIII domain, actively suppresses this alarm system. By recruiting the nuclear exosome to degrade RNA associated with R-loops, MYC limits the buildup of these RNA-DNA hybrids and prevents the activation of TLR3 and TBK1. Essentially, MYC is preventing the immune system from recognizing the presence of the tumor.
According to the published study, pancreatic tumor cells expressing a mutated MYC protein unable to bind RNA through RBRIII failed to suppress TBK1 autophosphorylation, a key indicator of TBK1 activation. While both normal MYC and the mutant protein stimulated cell proliferation in laboratory settings, only the normal MYC protein effectively suppressed gene sets associated with innate immune signaling, including those related to NF-κB and interferon pathways.
This difference was particularly striking in animal models. In a mouse model of pancreatic cancer, tumors expressing normal MYC increased in size 24-fold over a period of 28 days. However, tumors expressing the RBRIII mutant shrank by 94 percent during the same timeframe—but only in mice with fully functioning immune systems.
Tumor Regression Relies on Immune Recognition
The in vivo experiments highlighted a critical finding: MYC’s RNA-binding function is not essential for cell proliferation in the lab, but it is absolutely necessary for sustaining tumor growth in a host with a functioning immune system.
According to , senior author Martin Eilers, the data suggest that allowing the immune system to recognize the tumor can trigger its regression. Deleting or mutating the RBRIII domain did not affect MYC’s ability to bind to DNA and activate its usual target genes. Instead, it disrupted MYC’s ability to suppress the accumulation of RNA-DNA hybrids derived from R-loops on TLR3.
Further analysis revealed that cells expressing the RBRIII mutant accumulated higher levels of R-loops within genes regulated by MYC. These RNA-DNA hybrids then activated TLR3, leading to the activation of TBK1 and downstream immune signaling. The authors propose that MYC’s binding to RNA is a stress response that protects tumors from immune destruction by preventing the formation of immunogenic RNA species that would trigger innate immune defenses.
This discovery separates MYC’s role in promoting tumor growth from its role in helping cancer cells evade the immune system at a mechanistic level. Instead of attempting to shut down MYC entirely—a strategy that has proven challenging due to its importance in normal cell function—the findings suggest that selectively targeting its RNA-binding capacity could expose tumors to immune attack without disrupting its essential transcriptional activity.
