Loss of the Y chromosome drives basal identity and metastatic potential via epigenetic reprogramming in pancreatic cancer

  1. Madeleine Dorsch
  2. Felix E. G. Beaudry
  3. Anna K. Baginska
  4. Nancy Meyer
  5. Anne Petzold
  6. Peihua Zhao
  7. Belen Otero-Carrasco
  8. Kazeera Aliar
  9. Sebastian Urban
  10. Julia Zummack
  11. Jennifer Jung
  12. Johanna M. Hölken
  13. Ningjun Duan
  14. Laura Godfrey
  15. Mei-Ju May Chen
  16. Kathleen Schlüter
  17. Katyayni Ganesan
  18. Florian Over
  19. Thomas J. Y. Kono
  20. Hans-Ulrich Schildhaus
  21. Katja Steiger
  22. Roland F. Schwarz
  23. Elisabeth Hessmann
  24. Günter Schneider
  25. Jens T. Siveke
  26. John P. Neoptolemos
  27. Teresa Peccerella
  28. Maria Llamazares-Prada
  29. Alexander Schramm
  30. Christoph Plass
  31. Florian Rambow
  32. Faiyaz Notta
  33. Barbara T. Grünwald
  34. Barbara M. Grüner
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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.

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  2. Version published to 10.64898/2026.10.06.756936v2 on bioRxiv
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  6. Version published to 10.64898/2026.10.06.756936v1 on bioRxiv