Pancreatic cancer is an aggressive, highly lethal malignancy, with some of the highest mortality rates of all major cancers. In fact, per the Pancreatic Cancer Action Network (PCAN), pancreatic cancer remains the only major cancer with a five-year survival rate below 20 percent. PCAN cites several factors driving pancreatic cancer’s low survival rate, including a “critical gap in early detection, effective treatment options, and research investment.” However, pancreatic cancer cells also have a unique way of evading the immune system, proliferating with the help of the cancer-driving protein MYC.
A recent study published in the journal Cell explored a new way to attack pancreatic cancer cells: targeting a key MYC RNA-binding mechanism that helps tumors evade the immune system. Read on for an overview of the research, which has shown promising results in animal models.
A Hyper-Focused Approach to Treating Pancreatic Cancer
The study, published on January 22, focused on the MYC proto-oncogene, a protein associated with cancer biology. The protein drives cell division, leading to the proliferation of aggressive cancers like pancreatic cancer. Per the study, these tumors “depend on elevated MYC expression throughout their lifetime.”
MYC-driven tumors often fail to trigger an immune response — in essence, shielding themselves from immune detection — which makes treatment difficult. Scientists have made “numerous attempts to target MYC for tumor therapy,” the study notes. However, scientists have failed to identify how tumors with high MYC activity, like those associated with pancreatic cancer, manage to avoid immune-system detection. The new study focused on disabling this immune-shielding ability in animal models.
MYC: The “Shield” Enabling Cancer Growth
First, the team worked to identify how MYC evaded immune system detection. Through a series of cross-linking and immunoprecipitation (CLIP) experiments in K562 chronic myeloid leukemia cells, the researchers discovered something remarkable: MYC has a dual function. Experts have long understood the protein’s known function of binding to DNA and activating growth-promoting genes; however, the study identified that MYC has a second function when a cell is under stress. In these cases, MYC binds to newly formed RNA molecules rather than DNA.
When MYC binds to RNA, several things happen. First, MYC proteins form dense groupings called multimers. These clusters act as biomolecular condensates, organizing and drawing in other proteins, including the RNA exosome complex. “The exosome complex then breaks down cellular waste products in a very targeted manner,” the researchers wrote in a press release, adding that the complex focuses largely on “so-called RNA-DNA hybrids.” These hybrids are defective, and “normally act like a loud alarm signal inside the cell, [signaling] to the immune system that something is wrong.” In other words, by breaking down these hybrids, MYC effectively shuts down the cellular alarm system before it’s detected by immune defenses. The immune system never recognizes the tumor as a threat, and tumor growth continues unfettered.
The next step was clear: the researchers needed to alter MYC so it could no longer bind RNA, effectively disabling its second role and the “camouflage” it provided to cancer cells.
A “Targeted Strike” Attacking Tumors in Animal Models
Moving forward, the team worked with a p53/KRAS-driven (“KPC”) mouse model of pancreatic ductal adenocarcinoma (PDAC). The team genetically modified the RNA-binding region of MYC to prevent it from blocking the alarm pathway. “While pancreatic tumors with normal MYC increased in size 24-fold within 28 days, tumors with a defective MYC protein collapsed during the same period and shrank by 94 percent,” study lead Martin Eilers said in the press release, noting that immune activity was essential for the tumor collapse.
What’s next for this research? “Instead of completely switching off MYC, future drugs could specifically inhibit only its ability to bind RNA,” Eilers noted. “This would potentially leave its growth-promoting function untouched, but lift the tumor’s cloak of invisibility.”
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Moving forward, researchers will need to dive deeper into MYC mechanisms; for example, how MYC’s RNA-binding activity shapes the tumor’s local environment. While further research is needed, these findings could mark a major turning point in cancer treatment, particularly for aggressive cancers like pancreatic tumors.
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