PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer
Phosphoinositide kinases generate distinct phosphoinositides that regulate pathways to support tumorigenesis. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. We identify PI5P4Kα as a critical dependency to support the unique metabolic demands of PDAC cells through its key role in the acquisition of essential metabolic substrates, including glucose and iron. Our data show that inhibition of PI5P4Kα creates a metabolic bottleneck that PDAC cells cannot overcome through adaptive shifts, leading to cancer-specific apoptotic cell death that is reversible by iron supplementation. Notably, we find that PI5P4Kα knockdown suppresses tumor growth in a xenograft mouse model of PDAC. These results not only illuminate the mechanistic underpinnings of PI5P4Kα function in PDAC but also position it as a promising therapeutic target for this disease.
Authors
- David A. Scott (ORCID: https://orcid.org/0000-0002-8668-2449)
- Shea Grenier (ORCID: https://orcid.org/0000-0002-7686-5524)
- Cheska Marie Galapate (ORCID: https://orcid.org/0000-0002-7995-1663)
- Rabi Murad (ORCID: https://orcid.org/0009-0004-5297-8307)
- Alicia Llorente Lope (ORCID: https://orcid.org/0000-0002-6056-0566)
- Yoav Altman (ORCID: https://orcid.org/0000-0001-6075-1111)
- Ryan M. Loughran (ORCID: https://orcid.org/0000-0002-6384-1662)
- Brooke M. Emerling (ORCID: https://orcid.org/0000-0002-2168-4582)
- Gurpreet K. Arora (ORCID: https://orcid.org/0000-0003-0366-311X)
- C. Zhang
- Chantal Pauli (ORCID: https://orcid.org/0000-0001-9621-8511)
- Guillem Lambies
- Taylor Anderson (ORCID: https://orcid.org/0009-0004-4379-918X)
- Sophia Crabtree
- Cosimo Commisso (ORCID: https://orcid.org/0000-0002-7884-9210)
- Kyanh Ly (ORCID: https://orcid.org/0009-0004-9173-2609)
- Ling Li (ORCID: https://orcid.org/0000-0003-0083-6978)
- B Portillo
Institutions
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- University Hospital of Zurich (CH)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1016/j.celrep.2025.116199
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Cancer Society
- National Institutes of Health
- National Cancer Institute
- National Institute of General Medical Sciences
- Basic Research Laboratory