Researchers have known that in up to one in 10 pancreatic cancer cases, some of the pancreatic cells appear to have lost their identity. Now, however, Maia-Silva and colleagues at CSHL have uncovered how the MED12 protein may play a critical role in this process.
The findings are published a study in Nature Genetics.
“This is bizarre. You see pancreatic cancer, which usually somewhat resembles the original organ, losing those features and basically becoming akin to skin or esophagus—these other unrelated tissues,” explains Diogo Maia-Silva, PhD, a former postdoc at Cold Spring Harbor Lab (CSHL) and now at Massachusetts General Hospital.
Now, however, Maia-Silva and colleagues at CSHL just published a study in Nature Genetics that details how the MED12 protein may play a critical role in this process. While the discovery is notable in and of itself, it also builds on decades of CSHL research.
Key discoveries at CSHL
Twenty-five years ago, Alea Hills, PhD, discovered that p63 is important for the formation of normal basal cells—small cells in the lower part of the epidermis. Later research from another CSHL professor. Christopher Vako, PhD, found that this protein can also cause pancreatic cancer to become basal-like. Exactly how was unclear. Maia-Silva joined Vakoc’s lab in 2018, wanting to continue this investigation. Because p63 is notoriously difficult to target with drugs, he wondered which other molecules it might work with to confuse cells.
With his colleagues, he developed a method to screen the entire genome of basal-like cancer cells and rank which genes were most important for maintaining their new identity. In all his tests, MED12 rose to the top. This gene contains instructions for making the MED12 protein, one of about 25 in a complex that regulates gene activity.“The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder, and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC),” write the investigators in their current paper.
Powerful regulator
“This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements.
“Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.”
“That was unexpected because it’s part of this broad complex, but [most] other members of the complex didn’t show up. Despite being part of this general machinery of the cell, [MED12] has some unique property that makes it more important for basal biology,” said Maia-Silva.
Further tests showed that MED12 and p63 bind directly to each other. This suggests that each may be required to turn pancreatic cells basal-like. If researchers could one day figure out how to stop this interaction, it’s possible they could prevent pancreatic cancer from going basal.
But Maia-Silva is quick to note, this isn’t “something that can be easily done.” Still, “this is exciting,” he adds.
The finding is a first step toward blocking the pathway.
