Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • ASCI Milestone Awards
    • Video Abstracts
    • Conversations with Giants in Medicine
  • Reviews
    • View all reviews ...
    • Clinical innovation and scientific progress in GLP-1 medicine (Nov 2025)
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • ASCI Milestone Awards
  • Video Abstracts
  • Conversations with Giants in Medicine
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis
Marina Lesina, Sonja Maria Wörmann, Jennifer Morton, Kalliope Nina Diakopoulos, Olga Korneeva, Margit Wimmer, Henrik Einwächter, Jan Sperveslage, Ihsan Ekin Demir, Timo Kehl, Dieter Saur, Bence Sipos, Mathias Heikenwälder, Jörg Manfred Steiner, Timothy Cragin Wang, Owen J. Sansom, Roland Michael Schmid, Hana Algül
Marina Lesina, Sonja Maria Wörmann, Jennifer Morton, Kalliope Nina Diakopoulos, Olga Korneeva, Margit Wimmer, Henrik Einwächter, Jan Sperveslage, Ihsan Ekin Demir, Timo Kehl, Dieter Saur, Bence Sipos, Mathias Heikenwälder, Jörg Manfred Steiner, Timothy Cragin Wang, Owen J. Sansom, Roland Michael Schmid, Hana Algül
View: Text | PDF
Research Article Oncology

RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis

  • Text
  • PDF
Abstract

Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.

Authors

Marina Lesina, Sonja Maria Wörmann, Jennifer Morton, Kalliope Nina Diakopoulos, Olga Korneeva, Margit Wimmer, Henrik Einwächter, Jan Sperveslage, Ihsan Ekin Demir, Timo Kehl, Dieter Saur, Bence Sipos, Mathias Heikenwälder, Jörg Manfred Steiner, Timothy Cragin Wang, Owen J. Sansom, Roland Michael Schmid, Hana Algül

×

Figure 5

Regulation of OIS by RelA is mediated by CXCL1.

Options: View larger image (or click on image) Download as PowerPoint
Regulation of OIS by RelA is mediated by CXCL1.
(A) Kras PDECs treated w...
(A) Kras PDECs treated with vehicle control (DMSO) or an NF-κB inhibitor (JSH-23) were plated for the senescence assay. Scale bars: 100 μm. Representative images are shown. (B) Conditioned media were collected from PDECs treated with DMSO or JSH-23 for cytokine array analysis. The boxed regions on the representative blot indicate the differentially secreted cytokines. (C) Quantitative analysis of B, representing the average of the pixel intensity of 2 independent experiments. Mean ± SD; *P < 0.05, **P < 0.005, ***P < 0.0005 by unpaired t test. (D) Quantification of SA-β-Gal staining in Kras PDECs treated with DMSO or 100 ng/ml CXCL1. Ratio of SA-β-Gal–positive Kras PDEC cultures to the total number of Kras PDECs was counted per ×100 optical high-power field (HPF). Mean ± SD; ***P < 0.0005 by unpaired t test. (E) Representative photomicrographs showing in situ Cxcl1 mRNA in ductal lesions (black arrowhead), in acinar cells (white arrowhead), and in immune cells (black arrow). Scale bars: 50 μm. (F) Representative SA-β-Gal staining. Scale bars: 100 μm. (G) Ratio of SA-β-Gal–positive cells to the total number of mPanIN cells in 18-week-old Kras RelA (5 mice) and Kras RelA IL-8tg (4 mice) was counted per ×200 optical field (HPF). Mean ± SD; n ≥ 28; ***P < 0.0001 by Mann-Whitney test; n, number of HPF. (H) Representative H&E staining. Scale bars: 100 μm. (I) Numbers of mPanINs were counted per ×200 optical HPF. Mean ± SD; n ≥ 3; *P < 0.05 by unpaired t test; N.D., not detectable; n, number of mice. (J) Representative immunohistological analysis for p53 and 2′,7′-dichlorofluorescein diacetate (DCFDA) from Kras RelA (n = 3) and Kras RelA IL-8tg (n = 3) mice. Scale bars: 50 μm. Quantification of p53 positivity shown at the right. Mean ± SD; *P < 0.05 by unpaired t test; n, number of mice.

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts