Abstract
Abstract C106: IMPACT restrains immuno-metabolic GCN1 signaling to govern pancreatic cancer metastasis
Cancer research (Chicago, Ill.), Vol.84(2_Supplement), pp.C106-C106
01/16/2024
DOI: 10.1158/1538-7445.PANCA2023-C106
Abstract
Introduction: Metastatic outgrowth and colonization requires that disseminated tumor cells simultaneously compensate for alterations in nutrient availability, counteract oxidative stress, and evade host innate and adaptive immune surveillance. The mechanistic underpinnings of how these vital processes are coordinated is not understood. Experimental procedures: Using intrasplenic injection (liver metastases) and tail vein injection (lung metastases), we employed a gain-of-function cDNA screen in mice to identify regulators of colonization. In doing so, we identified GCN1 signaling as indispensable to the disseminated pancreatic cancer cell. Summary of unpublished data: Specifically, we demonstrate that alterations in nutrient availability encountered in target organs (liver, lung) trigger pancreatic cancer cells to utilize GCN1 stress signaling to upregulate the expression of serine, folate, and methionine pathway biosynthetic enzymes together with amino acid transporters through the integrated stress response effector ATF4. These pathways act in concert to facilitate acquisition of metabolites critical for cellular functions including maintenance of redox homeostasis. Surprisingly, we found that GCN1 also functions in the nucleus, where it interacts with HNRNPK to destabilize the transcripts encoding natural killer (NK) cell activation ligands and key regulators of major histocompatibility complex (MHC) class I molecules. Intriguingly, we identified an endogenous protein rheostat, IMPACT, for GCN1’s dual functions and show that IMPACT expression is lost in human pancreatic metastases through DNA methylation. IMPACT overexpression in pancreatic cancer cell lines inhibited the integrated stress response effector ATF4 to retard nutrient uptake and activated the expression of NK cell ligands and MHC class I molecules to fuel anti-tumor immune responses. Conversely, IMPACT knockout enabled successful acquisition of metabolic intermediaries in response to nutrient alterations and suppressed anti-tumor immune response to accelerate metastatic outgrowth. Accordingly, bioinformatic analyses of human pancreatic cancer showed that while the expression of GCN1 increases in metastatic disease, the expression of IMPACT is lost, correlating with significantly shorter survival of GCN1-high, IMPACT-low expressing tumors. Finally, IMPACT overexpression synergized with immune checkpoint inhibitors in mice to eliminate macrometastases formation. Conclusion: In summary, we have identified IMPACT as an immunometabolic checkpoint that restrains GCN1-mediated metabolic plasticity and GCN1-mediated suppression of innate and adaptive immune surveillance. We propose that drugs that can restore IMPACT expression or IMPACT mimetic agents will have therapeutic value for patients with pancreatic cancer. Citation Format: Surajit Sinha, Abir Panda, Zeribe Nwosu, Rodrigo Neves Das, Xu Ke, Elke van Beek, Alexander J. Rossi, Reed I. Ayabe, James McDonald, Michael M. Wach, Samantha Ruff, Priyanka P. Desai, David Sun, Martha E. Teke, Emily A. Verbus, Areeba Saif, Shreya Gupta, Tahsin Khan, Leila Sarvestani, Carrie E. Ryan, Jacob Lambdin, Kirsten Remmert, Emily Smith, Kenneth Luberice, Stephie Lux, Imani A. Alexander, Tracey Pu, Allen Luna, Sarfraz R. Akmal, Shahyan Rehman, Ashley Rainey, Hanna Hong, Yuri Lin, Samantha Sevilla, Gasmi Billel, Sivasish Sindiri, Todd Prickett, King Chan, Eileen Li, Xiaolin Wu, Nicholas D. Klemen, Giorgio Trinchieri, Costas A. Lyssiotis, Jeremy Davis, Pankaj K. Singh, Steven A. Rosenberg, Michael B. Yaffe, Filippo Giancotti, Ethan M. Shevach, Jonathan M. Hernandez. IMPACT restrains immuno-metabolic GCN1 signaling to govern pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C106.
Details
- Title: Subtitle
- Abstract C106: IMPACT restrains immuno-metabolic GCN1 signaling to govern pancreatic cancer metastasis
- Creators
- Surajit Sinha - National Cancer InstituteAbir Panda - National Institute of Allergy and Infectious DiseasesZeribe Nwosu - University of MichiganRodrigo Neves Das - National Cancer InstituteXu KeElke van Beek - Utrecht UniversityAlexander J. Rossi - Rutgers, The State University of New JerseyReed I. Ayabe - The University of Texas MD Anderson Cancer CenterJames McDonald - Moffitt Cancer CenterMichael M. Wach - University of Pittsburgh Medical CenterSamantha Ruff - Ohio UniversityPriyanka P. Desai - National Cancer InstituteDavid Sun - National Cancer InstituteMartha E. Teke - Southwestern Medical CenterEmily A. Verbus - Cleveland ClinicAreeba Saif - The University of Texas Health Science Center at HoustonShreya Gupta - University of MinnesotaTahsin KhanLeila Sarvestani - National Cancer InstituteCarrie E. Ryan - University at Buffalo, State University of New YorkJacob Lambdin - George Washington UniversityKirsten Remmert - National Cancer InstituteEmily Smith - National Cancer InstituteKenneth Luberice - National Cancer InstituteStephie Lux - Northwestern UniversityImani A. Alexander - Rutgers, The State University of New JerseyTracey Pu - National Cancer InstituteAllen Luna - Vanderbilt UniversitySarfraz R. Akmal - Johnson UniversityShahyan Rehman - University of New HavenAshley Rainey - National Cancer InstituteHanna Hong - Cleveland Clinic Lerner College of MedicineYuri Lin - National Cancer InstituteSamantha Sevilla - National Cancer InstituteGasmi BillelSivasish Sindiri - National Cancer InstituteTodd Prickett - National Cancer InstituteKing Chan - Frederick National Laboratory for Cancer ResearchEileen Li - University of PittsburghXiaolin Wu - National Cancer InstituteNicholas D. Klemen - National Cancer InstituteGiorgio Trinchieri - National Cancer InstituteCostas A. Lyssiotis - University of MichiganJeremy Davis - National Cancer InstitutePankaj K. Singh - Oklahoma City UniversitySteven A. Rosenberg - National Cancer InstituteMichael B. YaffeFilippo Giancotti - Columbia UniversityEthan M. Shevach - National Institute of Allergy and Infectious DiseasesJonathan M. Hernandez - National Cancer Institute
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.84(2_Supplement), pp.C106-C106
- DOI
- 10.1158/1538-7445.PANCA2023-C106
- ISSN
- 1538-7445
- eISSN
- 1538-7445
- Publisher
- AMER ASSOC CANCER RESEARCH
- Language
- English
- Date published
- 01/16/2024
- Academic Unit
- Surgery
- Record Identifier
- 9985224410702771
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