Hepatocytes promote liver metastasis of pancreatic cancer by providing serine
8 affiliations
- 1Department of Radiation Oncology, New York University Grossman School of Medicine, New York, NY USA
- 2Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY USA
- 3Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 4Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY USA
- 5Department of Surgery, New York University (NYU) Grossman School of Medicine and NYU Langone Health, New York, NY USA
- 6Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE USA
- 7Department of Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- 8Department of Pathology, New York University Grossman School of Medicine, New York, NY USA
Abstract
The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3–5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron–tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5–CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K–AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5–CXCR2–PI3K–AKT–FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell–hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.
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BibTeX
@article{ganguly2026hepatocytes,
title = {{Hepatocytes promote liver metastasis of pancreatic cancer by providing serine}},
author = {Koelina Ganguly and Keisuke Yamamoto and Jason Rodencal and Joel Encarnacion-Rosado and Albert S. W. Sohn and Douglas E. Biancur and Elaine Y. Lin and Ruohong Wang and Carolina Alcantara Hirsch and Anthony Sorrentino and Elshaddai Z. White and Paul M. Grandgenett and Michael A. Hollingsworth and Miwako Kakiuchi and Richard Possemato and Dafna Bar-Sagi and Mitsuhiro Fujishiro and Alec C. Kimmelman},
journal = {Nature},
year = {2026},
month = sep,
doi = {10.1038/s41586-026-11051-z},
url = {https://doi.org/10.1038/s41586-026-11051-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Hepatocytes promote liver metastasis of pancreatic cancer by providing serine
AU - Koelina Ganguly
AU - Keisuke Yamamoto
AU - Jason Rodencal
AU - Joel Encarnacion-Rosado
AU - Albert S. W. Sohn
AU - Douglas E. Biancur
AU - Elaine Y. Lin
AU - Ruohong Wang
AU - Carolina Alcantara Hirsch
AU - Anthony Sorrentino
AU - Elshaddai Z. White
AU - Paul M. Grandgenett
AU - Michael A. Hollingsworth
AU - Miwako Kakiuchi
AU - Richard Possemato
AU - Dafna Bar-Sagi
AU - Mitsuhiro Fujishiro
AU - Alec C. Kimmelman
PY - 2026
DA - 2026/09/23
JO - Nature
DO - 10.1038/s41586-026-11051-z
UR - https://doi.org/10.1038/s41586-026-11051-z
AB - The liver is the primary site of metastasis in pancreatic ductal adenocarcinoma (PDAC), and liver metastases are a major cause of mortality1,2. Nutrient availability in the metastatic niche influences colonization efficiency; however, the metabolic heterogeneity of disseminated tumour cells can also reshape the local microenvironment3–5. Loss of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine biosynthesis, is observed in nearly 40% of PDACs, and renders these cells dependent on exogenous serine (exSer)6. Although a neuron–tumour metabolic cross-talk supports exSer-dependent PDAC cells at the primary site6, it remains unclear how these cells adapt to the metastatic liver niche. Here we show that exSer-dependent PDAC cells reprogram neighbouring hepatocytes through a CXCL5–CXCR2 axis. Activation of CXCR2 in hepatocytes promotes PI3K–AKT signalling, leading to the sequestration of FOXO3A in the cytoplasm and derepression of PHGDH transcription, thereby enhancing serine production in hepatocytes. This hepatocyte-derived serine supports the outgrowth of exSer-dependent PDAC liver metastases. Accordingly, genetic or pharmacological inhibition of individual nodes within the CXCL5–CXCR2–PI3K–AKT–FOXO3A axis, or hepatocyte-specific deletion of Phgdh or Cxcr2, markedly reduces the liver-metastasis burden in mice and prolongs survival, particularly when dietary serine is restricted. Our findings reveal a cancer cell–hepatocyte metabolic cross-talk and identify therapeutic targets for exSer-dependent PDAC liver metastases.
SN - 0028-0836
SN - 1476-4687
ER -