A series of recently published studies have provided new insights into the molecular, genetic, and metabolic changes that occur during the earliest stages of pancreatic cancer development. The research, conducted by independent teams, examined precancerous lesions, genetic alterations, and cellular environments in the pancreas, offering a more detailed understanding of how the disease may initiate and progress.
Genetic Alterations in Early Lesions
Researchers at the Johns Hopkins Kimmel Cancer Center and its Ludwig Center analyzed genetic data from over 800 pancreatic tumors and precancerous lesions. Their findings, published in Cancer Discovery, indicate that extra copies of a specific segment of chromosome 1q are among the most frequent chromosomal changes in pancreatic ductal adenocarcinoma (PDAC). Whole-genome sequencing data from 535 pancreatic cancers showed chromosome 1q gains in nearly 40% of cases.
The team identified two small regions within the duplicated segment that contain genes, including NCSTN and PSEN2, which encode subunits of the γ-secretase complex. The expression of these genes correlated with the presence of the chromosomal gains.
Analysis of 267 precancerous lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs), revealed that chromosome 1q gains were rare in low-grade PanINs but common in high-grade lesions. In many high-grade lesions, these gains appeared independently of other chromosomal abnormalities or mutations in known pancreatic cancer driver genes, suggesting this duplication may be an early step in tumor evolution.
Molecular Profiling of Pancreatic Precancer
A separate study, also published in Cancer Discovery, examined the molecular and cellular changes in PanIN and PDAC using spatial transcriptomics and single-cell RNA sequencing. Researchers analyzed healthy donor pancreata, PanIN-containing samples, PDAC samples, and adjacent-normal pancreas tissue.
Findings showed that PanIN epithelial cells exhibited progressive molecular changes resembling cancer cells, including increased activity in the RAS/MAPK pathway, inflammatory pathways, hypoxia, and metabolic changes. Markers such as JAK/STAT3 signaling, KRT17, and WNT7A were elevated in poorly differentiated tissues.
In contrast, the surrounding stroma of PanIN lesions closely resembled healthy pancreatic tissue. Plasma cells were found near PanIN lesions, while macrophages remained distant. In tumor tissues, macrophages were clustered near cancer cells.
A tumor-enriched fibroblast population expressing SMA and LRRC15 was associated with poor prognosis. The study also noted that over 60% of healthy donor pancreata contained PanIN lesions, indicating these precursors are common but rarely progress to cancer.
Cellular Architecture of the Healthy Pancreas
A team at the Free University of Brussels (VUB) mapped the healthy human pancreas at cellular resolution. The research, published in the journal Gut, identified a layered structure in large pancreatic ducts containing a rare cell group with properties previously associated only with aggressive pancreatic cancer cells.
Comparison with patient tissue showed that in PDAC, the original cell organization is lost. In the rarer adenosquamous carcinoma (ASCP), the specific cell types and spatial structure from the healthy pancreas are preserved.
Metabolic Pathways in Disease Progression
A study published in Nature Metabolism investigated cellular pathways that influence metabolic changes during the progression from acinar-to-ductal metaplasia to cancer. Researchers conducted RNA-sequencing to identify cellular pathways important for metaplasia and precancerous lesions, finding elevated levels of two enzymes: glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1).
Using mouse models, the team observed that decreased activity of G6PD increased the number of precancerous lesions. Similar results were found in models lacking ME1. Both enzymes produce NADPH, a molecule involved in lipid and nucleic acid synthesis and in reducing reactive oxygen species (ROS). Lower levels of these enzymes in pancreatic cells correlated with higher levels of ROS. The formation of precancerous lesions was preventable by treating cells or animals with antioxidants. These results were consistent in pancreatic tissues from human donors.
A key finding was that while both enzymes produce NADPH, only the loss of ME1 led to progression into cancer. Future research will focus on identifying other enzymes that may influence cellular NADPH levels.
Implications and Future Research
The studies collectively suggest that the initial stages of pancreatic cancer involve a combination of genetic duplications, molecular changes in epithelial cells, and specific metabolic shifts. The findings may lead to new targeted therapies, improved diagnostics, and earlier detection methods. Further functional studies are planned to confirm the biological mechanisms identified.