Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant cells within an excessive tumor microenvironment (TME) consisting of extracellular matrix (ECM), fibroblasts, immune cells, and endothelial cells. Research conducted in recent years has particularly focused on cancer-associated fibroblasts (CAFs) which represent the most prominent cellular component of the desmoplastic stroma. Here, we review the complex crosstalk between CAFs, tumor cells, and other components of the TME, and illustrate how these interactions drive disease progression. We also discuss the emerging field of CAF heterogeneity, their tumor-supportive versus tumor-suppressive capacity, and the consequences for designing stroma-targeted therapies in the future.

Aging of the central nervous system (CNS) leads to motoric and cognitive decline and increases the probability for neurodegenerative disease development. Astrocytes fulfill central homeostatic functions in the CNS including regulation of immune responses and metabolic support of neurons and oligodendrocytes. In this study, we investigated the effect of redox imbalance in astrocytes by using a conditional astrocyte‐specific SOD2‐deficient mouse model (SOD2^ako) and analyzed these animals at different stages of their life. SOD2^ako mice did not exhibit any overt phenotype within the first postnatal weeks. However, already as young adults, they displayed progressive motoric impairments. Moreover, as these mice grew older, they exhibited signs of a progeroid phenotype and early death. Histological analysis in moribund SOD2^ako mice revealed the presence of age‐related brain alterations, neuroinflammation, neuronal damage and myelin impairment in brain and spinal cord. Additionally, transcriptome analysis of primary astrocytes revealed that SOD2 deletion triggered a hypometabolic state and promoted polarization toward A1‐neurotoxic status, possibly underlying the neuronal and myelin deficits. Conclusively, our study identifies maintenance of ROS homeostasis in astrocytes as a critical prerequisite for physiological CNS aging.

Pancreatic stellate cells (PSCs) are resident cells in the exocrine pancreas which contribute to pancreatic fibrogenesis and inflammation. Studies on NF-κB in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Here we show a protective immunomodulatory function of NF-κB in PSCs. Conditional deletion of NEMO (IKKγ) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged with caerulein, NEMO^ΔCol1a2 mice show an exacerbated autoimmune phenotype characterized by increased infiltration of eosinophils, B and T lymphocytes with reduced latency period. Transcriptomic profiling shows that NEMO^ΔCol1a2 mice display molecular signatures resembling autoimmune pancreatitis patients. Mechanistically, we show that PSC^ΔNEMO cells produce high levels of CCL24 ex vivo which contributes to eosinophil recruitment, as neutralization with a CCL24 antibody abolishes the transwell migration of eosinophils. Our findings uncover an unexpected immunomodulatory role specifically of NF-κB in PSCs during pancreatitis.

Traumatic brain injury (TBI) is a complex condition in which multiple pathophysiological mechanisms influence the course of the disease. After the initial mechanical impact, neuroinflammatory reactions of glial cells along with infiltrating peripheral immune cells determine the overall clinical outcome. However, these secondary processes and their molecular determinants promoting either beneficial or detrimental consequences are not well-defined. Here, we show that TBI-mediated NF-κB activation in astrocytes impairs their homeostatic functions, amplifies the post-traumatic neuroimmune response and disturbs the multicellular CNS scar development in a male mouse model of TBI. Our results further demonstrate a specific deficit in the formation of the glial limitans border and establish that paracrine signaling pathways induced by NF-κB-activated astrocytes can prevent a beneficial restoration of the CNS integrity after TBI. These findings enhance our understanding on the NF-κB-mediated post-traumatic pathophysiology and provide information on future targeted therapies to improve TBI outcome.

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.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by dense stroma, immune suppression, and therapy resistance. While canonical NF-κB signaling has been extensively studied in PDAC, the non-canonical pathway and its key kinase, NF-κB–inducing kinase (NIK), remain less characterized. Here, we employed genetically engineered mouse models, including Pdx1-Cre; KRAS ^G12D (KC), Pdx1-Cre; KRAS ^G12D ; p53 ^fl/fl (KPC), and their NIK-deficient counterparts (KNiC and KPNiC). To mimic inflammation-driven tumorigenesis observed in human PDAC, we administered cerulein in the KC and KNiC mice to induce pancreatitis and promote lesion progression. We found that NIK deletion accelerated lesion formation, progression to high-grade PanINs and invasive carcinoma in both KC and KPC backgrounds. Despite similar tumor grade and burden at endpoint, KPNiC mice exhibited shortened survival compared to controls, indicating that NIK acts as a tumor-suppressor and limits early-stage tumor progression. Mechanistically, NIK loss was associated with elevated ERK signaling that increased lesion cell proliferation, and also reduced acinar cell death following pancreatitis. In the tumor microenvironment, NIK deletion promoted myofibroblast activation and enrichment of myCAF-associated gene expression, likely through secondary activation of canonical NF-κB and pro-fibrotic signaling pathways such as TGF-β, Wnt, and FGF. Finally, increased IL6–STAT3 signaling and neutrophil infiltration were observed, suggesting broader immunostromal remodeling in the absence of NIK. Consistent with these findings, analysis of TCGA-PAAD data showed that low NIK expression correlates with poor overall survival in human PDAC. These findings reveal a tumor-suppressive role of NIK in pancreatic cancer and underscore the need for caution in targeting NF-κB signaling, as balanced pathway activity appears critical for regulating early tumor progression and microenvironmental interactions in PDAC.