Expression of IMPACT curtails metabolic plasticity and augments NK cell killing to abrogate metastatic growth

Surajit Sinha, National Cancer Institute, United States.
Abir Kumar Panda, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States.
Rodrigo Xavier das Neves, University of Pittsburgh, Pittsburgh, PA, United States.
Zeribe C. Nwosu, Cornell University, Ithaca, United States.
Ke Xu, Boston University, Boston, United States.
Elke van Beek, Memorial Sloan Kettering Cancer Center, United States.
Priyanka P. Desai, National Institutes of Health, United States.
Sivasish Sindiri, National Institutes of Health, Bethesda, MD, United States.
Sruthi Chempati, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States.
Kirsten Remmert, National Institutes of Health, United States.
Billel Gasmi, National Cancer Institute, BETHESDA, Maryland, United States.
Linda Bojmar, Linköping University, Linköping, Sweden.
Constantinos Zambirinis, Linköping University, Linköping, Sweden.
Alexander J. Rossi, Rutgers, The State University of New Jersey, United States.
Reed I. Ayabe, University of California, Irvine, Orange, CA, United States.
Michael M. Wach, Moffitt Cancer Center, Tampa, FL, United States.
James D. McDonald, National Institutes of Health, United States.
Samantha M. Ruff, University of Virginia, Charlottesville, United States.
Emily A. Verbus, Cleveland Clinic, United States.
Areeba Saif, National Institutes of Health, Bethesda, MD, United States.
Alyssa V. Eade, National Cancer Institute, Bethesda, Maryland, United States.
Carolina M. Larrain, National Cancer Institute, Bethesda, Maryland, United States.
Lindsay R. Friedman, National Cancer Institute, Bethesda, Maryland, United States.
Shreya Gupta, National Institutes of Health, United States.
Alok Ranjan, National Institutes of Health, United States.
Martha E. Teke, The University of Texas Southwestern Medical Center, United States.
Tahsin M. Khan, Icahn School of Medicine at Mount Sinai, United States.
Tracey Pu, National Institutes of Health, Bethesda, MD, United States.
Amber Leila Sarvestani, National Institutes of Health, Bethesda, MD, United States.
Carrie E. Ryan, University at Buffalo, State University of New York, United States.
Jacob T. Lambdin, George Washington University, United States.
Kenneth Luberice, University of Florida Health, Jacksonville, FL, United States.

Document Type

Journal Article

Publication Date

7-31-2025

Journal

Cancer discovery

DOI

10.1158/2159-8290.CD-24-1055

Abstract

Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D/TP53R273H pancreatic cells to identify the RNA binding protein GCN1 as integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the ISR to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules, and natural killer (NK) ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade (ICB).

Department

School of Medicine and Health Sciences Resident Works

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