2. Academic Validation
  3. PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer

PI5P4Kα promotes glucose and iron acquisition to support metabolic fitness in pancreatic cancer

  • Cell Rep. 2025 Sep 23;44(9):116199. doi: 10.1016/j.celrep.2025.116199.
Gurpreet K Arora 1,  Ryan M Loughran 1,  Kyanh Ly 1,  Cheska Marie Galapate 1,  Alicia Llorente 1,  Taylor R Anderson 1,  Cynthia Y Zhang 1,  Shea F Grenier 1,  Li Ling 1,  Sophia Crabtree 1,  Guillem Lambies 1,  Chantal Pauli 2,  David A Scott 3,  Yoav Altman 4,  Benji Portillo 4,  Rabi Murad 1,  Cosimo Commisso 5,  Brooke M Emerling 6
Affiliations

Affiliations

  • 1 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 2 Department of Pathology and Molecular Pathology, University Hospital Zürich and the University of Zurich (UZH), 8006 Zurich, Switzerland.
  • 3 Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 4 Flow Cytometry Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 5 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: ccommisso@sbpdiscovery.org.
  • 6 Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. Electronic address: bemerling@sbpdiscovery.org.
PMID: 40884794 DOI: 10.1016/j.celrep.2025.116199
Abstract

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.

Keywords

CP: Cancer; CP: Metabolism; PI5P4K; PIP4K; apoptosis; autophagy; glucose; iron; metabolism; nutrient stress; pancreatic cancer; phosphoinositide kinase.

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