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Updated: Mar 17, 2026
Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
Published on: February 11, 2019
RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis
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.
Insights
Nuclear RelA reinforces oncogene-induced senescence (OIS) to suppress pancreatic cancer. Its inactivation accelerated tumor growth by disrupting the senescence-associated secretory phenotype (SASP), highlighting the RelA/CXCL1/CXCR2 axis in tumor surveillance.
Area of Science:
- Oncology
- Cellular Biology
- Molecular Mechanisms of Cancer
Background:
- Oncogene-induced senescence (OIS) is a tumor suppression mechanism crucial in pancreatic ductal adenocarcinoma (PDAC) development.
- The regulatory mechanisms of OIS in PDAC are not well understood.
- Understanding these mechanisms is vital for developing new therapeutic strategies against PDAC.
Purpose of the Study:
- To investigate the role of nuclear RelA in regulating OIS during pancreatic carcinogenesis.
- To elucidate the molecular pathways involving RelA, SASP, CXCL1, and CXCR2 in PDAC development.
- To assess the therapeutic potential of targeting the RelA/CXCL1/CXCR2 axis for PDAC surveillance.
Main Methods:
- Utilized the Kras mouse model of PDAC.
- Employed genetic inactivation and pharmacological tools to manipulate RelA and CXCR2.
- Analyzed gene transcription of SASP factors, including CXCL1.
- Examined pancreatic tissue from both mice and human specimens.
Main Results:
- Nuclear RelA was found to reinforce OIS and inhibit carcinogenesis in the Kras mouse model.
- RelA inactivation accelerated pancreatic lesion formation by abrogating SASP gene transcription.
- RelA activation promotes OIS via CXCL1-mediated CXCR2 activation.
- Pancreas-specific inactivation of CXCR2 in Kras mice prevented OIS, increased tumor proliferation, and decreased survival.
- Reduced CXCR2 levels correlated with advanced neoplastic lesions in human pancreatic tissues.
- Disabling OIS in Kras mice revealed a dual role for RelA signaling in promoting tumor proliferation.
Conclusions:
- RelA plays a pivotal role in regulating OIS in preneoplastic lesions of the pancreas.
- The RelA/CXCL1/CXCR2 signaling axis is identified as an essential mechanism for tumor surveillance in PDAC.
- Targeting this axis may offer a novel therapeutic strategy for pancreatic cancer prevention and treatment.
