Introduction

Pancreatic cancer is a formidable foe, with a mortality rate that remains stubbornly high despite advances in surgical and chemo-radio-targeted-immuno- therapeutics. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, the match maker of inflammation and cancer, has emerged as a key player in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), but much remains unknown about the role of individual NF-κB transcription factors in this deadly disease.^1,2 Here, we shed light on the pivotal but paradoxical functions of c-Rel in PDAC, revealing its impact on survival, metastasis, epithelial to mesenchymal transition (EMT), cancer stem cell-ness (CSC-ness), and chemotherapy response. Our findings have important implications for future treatments as we continue to navigate the complex and context-specific role of c-Rel in pancreatic cancer.

Aims & Methods

To investigate the function of c-Rel in PDAC, we employed genetically engineered mouse models (GEMMs) that accurately mimic the human PDAC pathophysiology, allowing for precise control of genetic manipulations. Specifically, we utilised the Ptf1a-Cre;KrasG12D/+;Trp53f/f mouse model of mPDAC and analysed the histopathological effects of c-Rel knock-out and over-expression in cancer cells.² Furthermore, we isolated murine cancer cells for in-vitro and ex-vivo experiments to explore the underlying molecular mechanisms. Additionally, we evaluated our findings within a human PDAC cohort, providing clinical relevance to our results.

Results

Our results reveal intriguing insights into the role of c-Rel in mPDAC pathogenesis. We found c-Rel expression correlation with mPDAC progression, suggesting a potential oncogenic function. c-Rel overexpression led to enhanced undifferentiated tumor pathology along with epithelial to mesenchymal transition (EMT). Moreover, ECM remodeling and acquisition of cancer stem cell (CSC) characteristics are observed. ECM remodeling is accompanied by reduced collagen and enhanced fibronectin deposition. Additionally, unlike the conventional CSC markers such as CD44, CD133, CXCR4, Sca-1, and EpCAM, c-Rel overexpressing cells achieve CSC-ness via integrin-β3 surface expression.
Interestingly, Fibronectin deletion abolishes c-Rel mediated CSC-ness in vitro, but fails to rescue the reduced survival observed in c-Rel overexpression tumors in vivo. We found that c-Rel overexpression tumors retain Fibronectin supply in the tumor microenvironment, likely through an intricate paracrine signaling network. Paradoxically, both c-Rel knockout and overexpression cells metastasize more in transplantation models, while high c-Rel expression, although oncogenic, increases chemotherapy sensitivity in PDAC cells.
Concurrently, our histopathological analysis of c-Rel expression in a cohort of 144 PDAC patients revealed contrasting prognostic impacts on survival, depending on the surgical margin stratification. These findings highlight the complex and context-dependent role of c-Rel in PDAC, influencing various aspects of tumor behavior, including stemness, metastasis, chemotherapy response, and patient survival.

Conclusion

Taken together, our results shed light on the intricate and paradoxical functions of c-Rel in PDAC, epitomizing the context-specific protein activity influencing multiple facets of tumor biology. These findings have important implications for understanding the complexity of PDAC progression and may provide potential therapeutic targets for future interventions.

References

1. Kabacaoglu D, Ruess DA, Ai J, Algül H. NF-κB/Rel Transcription Factors in Pancreatic Cancer: Focusing on RelA, c-Rel, and RelB. Cancers (Basel). 2019 Jul 4;11(7).
2. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol. 2011 Jul 19;12(8):715–23.
3. Kabacaoğlu D, Ruess DA, Görgülü K, Steiger K, Lesina M, Algül H. A Pancreas-Specific Ptf1a-Driven Cre Mouse Line Causes Paternally Transmitted Germline Recombination. Gastroenterology. 2021 Nov;161(5):1695–1697.e4.