Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of cancer and chances of survival are poor. Molecular triggers that result in PDAC remain unclear.
To better understand these molecular triggers of oncogenesis in the context of PDAC, a large international collaborative team led by scientists from Washington University, St. Louis, Baylor College of Medicine, Houston, and Johns Hopkins University, Baltimore, have analyzed the proteomes and genomes of 140 pancreatic cancers and compared the data to 67 normal surrounding tissues, and 9 pancreatic ductal tissues.
In addition to analyzing how the proteomes are modified through phosphorylation and glycosylation, the authors conduct methylation studies, whole-genome and whole-exome sequencing, and RNA and microRNA sequencing on the same tissues to achieve an integrated understanding of the effect of genomic changes on protein expression, signaling pathways, and biochemical modifications of proteins that have been synthesized. The authors use a multi-pronged approach to analyze cellular changes in tumors using identified molecular signatures and histology.
These findings are reported in the article, “Proteogenomic characterization of pancreatic ductal adenocarcinoma,” published in the journal Cell. This comprehensive and integrated proteogenomic characterization is a valuable resource for the development of early detection strategies and the identification of therapeutic targets for PDAC. It identifies several promising new targets for PDAC treatment and early diagnosis through a detailed examination of the tumors’ genes and proteins.
“The abundance of data produced in this study could aid the search for new ways to improve pancreatic cancer detection and treatment far into the future,” says co-author Ralph Hruban, MD, director of the Sol Goldman Pancreatic Cancer Research Center and professor of pathology at the Johns Hopkins University School of Medicine. “This study is a starting point to answer research questions that could revolutionize pancreatic cancer care.”
“Right now, patients with pancreatic cancer have very few options, and the wealth of data produced by this study could lead to new ways to fight this disease,” says study leader Hui Zhang, PhD, director of the Mass Spectrometry Core Facility and professor of pathology at the Johns Hopkins University School of Medicine.
“Despite decades of study, pancreatic cancer has remained a grim diagnosis,” says Hruban.
Patients diagnosed with PDAC have a less than 10% chance of surviving five years. In patients where the disease has spread to other regions of the body (metastasis), the median survival is less than a year. Due to the lack of early diagnostic symptoms and reliable methods for screening and early detection, most patients are diagnosed at a late stage when surgery is no longer possible, resulting in a poor prognosis.
“Although numerous studies have examined the genes of pancreatic tumors and identified several mutations linked to this disease,” adds Zhang, “these mutations cannot be targeted with drug therapies.” Immunotherapies against PDAC have not been very effective because these tumors don’t attract a significant immune attack.
To identify better therapeutic targets and markers for early detection of pancreatic cancer, Zhang, Hruban, Daniel Chan, PhD, director of the clinical chemistry division and professor of pathology, postdoctoral researcher Liwei Cao, PhD, and collaborators from Johns Hopkins and other international institutions take new multiomic approach, combining genomics, transcriptomics and proteomics.
The researchers confirm that pancreatic tumors are more likely to have mutations in several genes reported in earlier studies, including KRAS, TP53, CDKN2A and SMAD4. Comparing PDAC and normal cells, the team identifies 222 proteins that are expressed at a two-fold greater abundance in cancer cells. They also identify nearly 5,000 sites in these 222 proteins with increased phosphorylation and more than 1,700 sites with increased glycosylation—the addition of sugar molecules.
“Several glycosylated proteins are secreted from pancreatic cancer cells,” Zhang says, suggesting they could potentially be detected in the blood for early diagnosis.
Kinases generally represent hubs in the cellular proteome that modify the fate and function of several proteins by adding phosphate groups to them. The researchers identify PAK1 and PAK2—two kinases that are dysregulated in pancreatic cancer, and could offer previously unrecognized therapeutic targets. Several small molecule inhibitors are known to target PAK1, offering a potential path toward treating pancreatic tumors.
“Other protein differences between the cancer cells and normal tissue appear to be roadblocks that stymie immune system attack,” adds Zhang, suggesting new ways that these proteins could be targeted to mount an immune attack against PDAC tumors.
“Our study delineates the molecular features that drive the PDAC phenotypes and provides a rich bioinformatic resource for future hypothesis-driven translational research,” the authors note.