Pancreatic cancer, pancreas with PDAC, illustration

New research has unveiled a key relationship between two proteins that causes a unique subtype of pancreatic ductal adenocarcinoma cancer (PDAC) known as basal-like pancreatic cancer, which affects around 15% of PDAC patients. This subtype exhibits an unusual transformation, causing the pancreatic cells to take on characteristics akin to skin cells, resulting in an aggressive and often fatal form of cancer.

“Pancreatic cancer is horrific across the board, with only 10% of patients surviving for five years. Almost every basal-like pancreatic cancer patient is dead within one year,” said Christopher Vakoc from the Cold Spring Harbor Laboratory. This grim prognosis makes understanding and targeting this subtype an urgent priority.

Vakoc led a recent study published in Nature Genetics, which sheds light on the molecular mechanisms driving the transformation to a basal-like state. “We set out to develop a marker-based CRISPR screening method capable of revealing all genes needed to maintain basal identity in this disease,” he says. The team’s discovery centers around two proteins: MED12 and p63. “This is the first biochemical mechanism shown to cause this basal biology in pancreatic cancer,” noted Vakoc. Their research reveals that the interaction between MED12 and p63 is crucial for the development of basal-like pancreatic cancer, potentially opening new avenues for therapeutic intervention.

Vakoc elaborated, “Basal-like pancreatic cancer essentially involves ductal cells of the pancreas transforming to resemble skin cells. This transformation is associated with all the aggressive features that make this subtype so deadly.” The MED12 protein, a part of a complex that regulates gene activity, emerged as a key player in this process. Through an innovative screening method developed by the team, MED12 was identified as one of the top genes maintaining the basal-like identity of these cancer cells.

“This was very unexpected because MED12 is part of a broad complex, yet it showed a unique property making it more important for basal biology,” explained first author Diogo Maia-Silva. This discovery was significant because it provided a new target for potential therapies aimed at disrupting the MED12-p63 interaction, thereby preventing the basal-like transformation.

The implications of this research are profound. “Biochemical discoveries like this can be an entry point for rational drug development,” Vakoc emphasized. “We envision that a small molecule or chemical medicine could be invented to break the MED12-p63 interaction, reversing the aggressive transformation of these tumors.”

Vakoc also highlighted the innovative method used to uncover this critical interaction. “We developed a technology to measure how basal a pancreatic cancer cell is, using a high-throughput CRISPR-based screen,” he explained. This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. This allowed the team to perturb every gene in the genome and identify the key players in maintaining the basal-like state of these cancer cells. “Out of the 20,000 gene perturbations we screened for basal-like PDAC, the top two were for MED12 and p63.”

Vakoc explains this work tailors perfectly with the current focus on lineage plasticity in cancer—how, after therapy, a tumor that began as one type after encountering a therapy switches into another type. of cancer. “This is a major thread in oncology research today,” he adds.

For example, he cites that one of the standards of care in PDAC is treating with an androgen receptor blocker. While it may be effective for many years, the tumor can transform from prostate adenocarcinoma to prostate neuroendocrine carcinoma. “It’s like a complete shapeshift,” Vakoc says, “and this has become a major problem with clinical medicines in these shape-shifting tumors. What we have described in this publication is a technology to understand this at a very high resolution, very sophisticated kind of screen to understand this type of biology.”

Vakoc is enthused to apply this methodology to other cancers. The team already uses it in lung cancer, pediatric sarcoma, and leukemia studies. “We’re still trying to figure out the intricacies of how these tumors transform, but this research offers a promising starting point,” Vakoc reflects. “We’d like to turn this aggressive attribute into an Achilles’ heel for the tumor. It’s an exciting yet challenging path, but the potential benefits for patients with this lethal subtype of cancer are immense.”

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