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Deletion of NEMO Inhibits EMT and Reduces Metastasis in KPC Mice
Miltiadis Tsesmelis1, Kanishka Tiwary2, Katja Steiger3
1Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) remains a largely incurable cancer type. Its high mortality is attributed to the lack of efficient biomarkers for early detection combined with its high metastatic properties. The aim of our study was to investigate the role of NF-κB signaling in the development and metastasis of PDAC. We used the well-established KPC mouse model, and, through genetic manipulation, we deleted NF-κB essential modulator (NEMO) in the pancreata of KPC mice. Interestingly, NEMO deletion altered the differentiation status of the primary tumor but did not significantly affect its development. However, in the absence of NEMO, the median survival of the mice was prolonged by 13.5 days (16%). In addition, examination of the liver demonstrated that, whereas KPC mice occasionally developed liver macro-metastasis, NEMO deletion completely abrogated this outcome. Further analysis of the tumor revealed that the expression of epithelial-mesenchymal transition (EMT) transcription factors was diminished in the absence of NEMO. Conclusively, our study provides evidence that NF-κB is dispensable for the progression of high-grade PanINs towards PDAC. In contrast, NF-κB signaling is essential for the development of metastasis by regulating the gene expression program of EMT.
Insights
NF-κB signaling is crucial for pancreatic cancer metastasis, not primary tumor growth. Inhibiting NEMO in KPC mice prolonged survival and prevented liver metastasis by reducing epithelial-mesenchymal transition (EMT).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to late detection and high metastasis rates.
- Nuclear factor kappa B (NF-κB) signaling pathways are implicated in various cancers, but their specific role in PDAC metastasis is not fully understood.
Purpose of the Study:
- To investigate the role of NF-κB signaling, specifically the NF-κB essential modulator (NEMO), in PDAC development and metastasis.
- To determine if targeting NF-κB signaling can impact PDAC progression and survival.
Main Methods:
- Utilized the KPC mouse model for pancreatic cancer.
- Genetically manipulated KPC mice to delete NEMO in pancreatic tissue.
- Analyzed tumor development, differentiation status, survival rates, liver metastasis, and epithelial-mesenchymal transition (EMT) gene expression.
Main Results:
- NEMO deletion altered primary tumor differentiation but did not significantly affect tumor development.
- Median survival in KPC mice with NEMO deletion was prolonged by 13.5 days (16%).
- NEMO deletion completely abrogated liver macro-metastasis and diminished EMT transcription factor expression.
Conclusions:
- NF-κB signaling is dispensable for the progression of high-grade PanINs to PDAC.
- NF-κB signaling is essential for PDAC metastasis, primarily by regulating the EMT gene expression program.
