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Collaboration is at the heart of Huntsman Cancer Institute’s culture. Fueled by a dedication to our mission, laboratory scientists make progress each day toward understanding cancer from its beginnings. Recently, two studies by Huntsman Cancer Institute researchers made significant headway in two of the deadliest and most hard-to-treat cancers, lung and pancreatic.
When cells become cancerous, grow, and spread, different genes are switched on and off. This can cause tumor cells to change their identity and transition into other types of cells, called “lineage switching.” Eric Snyder, MD, PhD, a leader of this lung and pancreatic cancer research, explains, “A tumor’s cellular identity has a profound effect on its intrinsic malignant potential and on how it responds to treatment.”
Previously, Snyder showed that the molecule NKX2-1 controlled a lung cancer cell’s adoption of a new cellular identity. Specifically, the loss of NKX2-1 drove cancer cells to shed their lung identity and adopt a gastric identity.
These discoveries informed a new study of lung cancer by Snyder, Michelle Mendoza, PhD, and Benjamin Spike, PhD. Using cutting-edge gene expression analysis and genetically modified mice, the researchers found that NKX2-1 loss also changed how lung tumors responded to targeted therapy. A specific targeted therapy led to additional changes in cell identity, causing the cancerous lung cells to resemble cells that normally secrete digestive enzymes in the stomach. These changed tumor cells were indifferent to the drugs being given, potentially because their alternative identity uses different pathways to survive.
“This study tells us that targeted therapies, traditionally based primarily on a tumor’s genetics, can directly change tumor cell identity. This means we need to develop new drug combination strategies targeting vulnerabilities associated with the tumor’s identity and genetics,” says Snyder.
In the second study, Snyder and colleague Jay Gertz, PhD, studied pancreatic cancer. Pancreatic cancer has two major subtypes: basal-like and classical. The basal-like subtype has a worse prognosis than the classical subtype. The research demonstrated that a set of lineage specifiers (HNF4α, SIX4, and SIX1) regulated the identity of the pancreatic cancer cells. Importantly, HNF4α has the potential to be a drug target, and SIX4 and SIX1 interact with molecules that also respond to treatment.
Spike sums up the value of these findings: “This new insight into molecular drivers of identity change in lung and pancreatic cancer cells helps explain why these cancers are so difficult to treat. More importantly, it provides new opportunities for cancer treatment and discovery of curative therapies.”