Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer
Dorsch, M.; Beaudry, F. E. G.; Baginska, A. K.; Meyer, N.; Petzold, A.; Zhao, P.; Otero-Carrasco, B.; Aliar, K.; Urban, S.; Zummack, J.; Jung, J.; Hölken, J. M.; Duan, N.; Godfrey, L.; Chen, M.-j. M.; Schlüter, K.; Ganesan, K.; Over, F.; Kono, T.; Schildhaus, H.-U.; Steiger, K.; Schwarz, R.; Hessmann, E.; Schneider, G.; Siveke, J. T.; Neoptolemos, J. P.; Peccerella, T.; Llamazares-Prada, M.; Schramm, A.; Plass, C.; Rambow, F.; Notta, F.; Grünwald, B. T.; Grüner, B. M.
Show abstract
Loss of the Y chromosome (LOY) has been largely unexplored in pancreatic ductal adenocarcinoma (PDAC), and no mechanistic framework previously explained its role in tumor biology. We identify LOY as a recurrent, functionally consequential alteration affecting ~50% of male PDAC patients across two independent cohorts, with strong enrichment in advanced disease and, critically, in the basal subtype, establishing LOY as a clinically actionable biomarker. Comprehensive genomic profiling positions LOY as a distinct genetic event associated with TP53 mutations, implicating it in aggressive tumor evolution. Integrative analyses across bulk tumors, single-cell datasets and CRISPR-engineered PDAC models converge on epithelial-to-mesenchymal transition (EMT) as the dominant LOY-driven program. Y-chromosome deletion alone induces EMT transcriptional states, mesenchymal morphology and enhanced metastatic ability. Mechanistically, LOY disrupts epigenetic regulation through loss of Y-linked chromatin modifiers, reshaping DNA methylation at EMT- and basal-defining loci and reducing chemotherapy sensitivity. These findings establish LOY as a causal genetic driver of PDAC progression and a clinically accessible biomarker with direct therapeutic relevance.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Beta cells are essential drivers of pancreatic ductal adenocarcinoma development 94%
- An Essential Role for Argonaute 2 in EGFR-KRAS Signaling in Pancreatic Cancer Development 94%
- Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment 93%
Similar papers in this journal
- Genomic evolution of pancreatic cancer at single-cell resolution 94%
- Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer 93%
- Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma 92%
Similar papers in this journal
- TET2 drives 5hmc marking of GATA6 and epigenetically defines pancreatic ductal adenocarcinoma transcriptional subtypes 95%
- BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma 92%
- Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.