Researchers have found an epigenetic switch that pancreatic cancer cells use to protect themselves against genomic instability. In a study published in Cancer Research, the team reports that blocking the epigenetic regulator DPY30 triggered immune cell infiltration into pancreatic tumors in mice, sensitizing them to immunotherapy.
Frequently diagnosed at advanced stages, pancreatic cancer is often resistant to conventional therapies and shows limited response to immunotherapy. This leaves patients with few effective treatment options.
“As cancer biologists, we are intrigued by the remarkable ability of pancreatic cancer cells to tolerate genomic instability and sustained replication stress while continuing to proliferate and evade immune surveillance,” said Francesca Citron, PharmD, PhD, instructor of genomic medicine at The University of Texas MD Anderson Cancer Center and lead author of the study. “This paradox led us to investigate the adaptive mechanisms that enable cancer cells to buffer genomic instability, particularly by protecting replication forks and preventing catastrophic DNA damage.”
The researchers were interested in finding out whether epigenetic regulators may play a direct role in safeguarding the integrity of replication forks, where DNA is copied as cells divide. Under stress, DNA replication is typically disrupted, for instance as cancer cells continue dividing and accumulating mutations that result in genomic instability. However, Citron’s team discovered that pancreatic cancer cells rely on DPY30 to protect DNA replication forks under stress and continue multiplying in spite of genomic instability.
DPY30 belongs to a group of proteins that together form the WRAD/COMPASS complex, which is involved in epigenetics regulation. The study found that this component was able to switch the entire complex from playing a global epigenetics function to a localized role at stressed replication forks, where DPY30 stabilized.
“Historically, WRAD core components, particularly DPY30, have been primarily studied in the context of histone methylation and transcriptional regulation,” said Citron. “Our findings significantly expand this paradigm by demonstrating that these factors play a direct role in maintaining replication fork stability under conditions of stress. Importantly, we also establish a link between this mechanism and modulation of the tumor immune microenvironment, providing a conceptual bridge between replication stress and immune response.”
In a mouse model of pancreatic cancer, DPY30 inhibition destabilized replication forks, leading to increased genomic instability and activating inflammatory signaling pathways. This then triggered the recruitment of tumor-infiltrating lymphocytes and turned previously immunologically “cold” tumors into “hot” tumors that responded to immunotherapy.
“Inhibiting DPY30 leads to increased replication-associated DNA damage, which in turn robustly enhances immune signaling pathways,” said Citron. “This dual effect, on genome stability and immune activation, opens new therapeutic opportunities to impair replication fork protection while simultaneously stimulating anti-tumor immune responses.”
Furthermore, biopsies from pancreatic cancer patients showed that higher levels of DPY30 expression were associated with higher tumor grades, a poorer prognosis and lower response rates to immunotherapy. Together, these findings point at DPY30 as both a therapeutic target and a biomarker to stratify patients who are most likely to benefit from immunotherapy.
Going forward, the researchers plan to dive deeper into how HPY30 influences immune cell recruitment and activation within the tumor microenvironment. In parallel, they will be exploring pharmacological strategies to inhibit DPY30 and testing their efficacy in preclinical studies. Citron added: “Ultimately, our goal is to develop rational combination therapies that drive more effective and durable responses in patients.”
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