Genetic ablation of ketohexokinase C isoform impairs pancreatic cancer development
Ilaria Guccini,
Guanghui Tang,
Trang Thuy To,
Laura Di Rito,
Solange Le Blanc,
Oliver Strobel,
Mariantonietta D’Ambrosio,
Emiliano Pasquini,
Marco Bolis,
Pamuditha Silva,
Hasan Ali Kabakci,
Svenja Godbersen,
Andrea Alimonti,
Gerald Schwank,
Markus Stoffel
Affiliations
Ilaria Guccini
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
Guanghui Tang
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
Trang Thuy To
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
Laura Di Rito
Computational Oncology Unit, Department of Oncology, Istituto di Richerche Farmacologiche 'Mario Negri' IRCCS, 20156 Milano, Italy
Solange Le Blanc
European Pancreas Center, Department of General Surgery, Heidelberg University Hospital, Heidelberg, Germany
Oliver Strobel
European Pancreas Center, Department of General Surgery, Heidelberg University Hospital, Heidelberg, Germany
Mariantonietta D’Ambrosio
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), 6500 Bellinzona, Switzerland; Universita’ della Svizzera Italiana, 6900 Lugano, Switzerland
Emiliano Pasquini
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), 6500 Bellinzona, Switzerland; Universita’ della Svizzera Italiana, 6900 Lugano, Switzerland
Marco Bolis
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), 6500 Bellinzona, Switzerland; Bioinformatics Core Unit, Swiss Institute of Bioinformatics, TI, 6500 Bellinzona, Switzerland
Pamuditha Silva
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
Hasan Ali Kabakci
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
Svenja Godbersen
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
Andrea Alimonti
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), 6500 Bellinzona, Switzerland; Universita’ della Svizzera Italiana, 6900 Lugano, Switzerland; Department of Medicine, University of Padua, 35128 Padua, Italy; Department of Health Sciences and Technology (D-HEST) ETH Zurich, 8093 Zurich, Switzerland
Gerald Schwank
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland
Markus Stoffel
Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland; Corresponding author
Summary: Although dietary fructose is associated with an elevated risk for pancreatic cancer, the underlying mechanisms remain elusive. Here, we report that ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, is a driver of PDAC development. We demonstrate that fructose triggers KHK and induces fructolytic gene expression in mouse and human PDAC. Genetic inactivation of KhkC enhances the survival of KPC-driven PDAC even in the absence of high fructose diet. Furthermore, it decreases the viability, migratory capability, and growth of KPC cells in a cell autonomous manner. Mechanistically, we demonstrate that genetic ablation of KHKC strongly impairs the activation of KRAS-MAPK pathway and of rpS6, a downstream target of mTORC signaling. Moreover, overexpression of KHKC in KPC cells enhances the downstream KRAS pathway and cell viability. Our data provide new insights into the role of KHK in PDAC progression and imply that inhibiting KHK could have profound implications for pancreatic cancer therapy.
