Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming.

BACKGROUND & AIMS: Oncogenic Kirsten Rat Sarcoma virus (KRAS) is the hallmark mutation of human pancreatic cancer and a driver of tumorigenesis in genetically engineered mouse models of the disease. Although the tumor cell-intrinsic effects of oncogenic Kras expression have been widely studied, its role in regulating the extensive pancreatic tumor microenvironment is less understood. METHODS: Using a genetically engineered mouse model of inducible and reversible oncogenic Kras expression and a combination of approaches that include mass cytometry and single-cell RNA sequencing we studied the effect of oncogenic KRAS in the tumor microenvironment. RESULTS: We have discovered that non-cell autonomous (ie, extrinsic) oncogenic KRAS signaling reprograms pancreatic fibroblasts, activating an inflammatory gene expression program. As a result, fibroblasts become a hub of extracellular signaling, and the main source of cytokines mediating the polarization of protumorigenic macrophages while also preventing tissue repair. CONCLUSIONS: Our study provides fundamental knowledge on the mechanisms underlying the formation of the fibroinflammatory stroma in pancreatic cancer and highlights stromal pathways with the potential to be exploited therapeutically.

Cardiovascular Risk Associated With TNF Alpha Inhibitor Use in Patients With Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and pannus formation, with subsequent joint and cartilage degradation. Treatment commonly targets inflammatory cytokines, including tumor necrosis factor (TNF) alpha, which is a potent inflammatory cytokine required for cell signaling, regulation, and apoptosis, as well as for other cellular functions including immune response. TNF alpha inhibitors have demonstrated benefits in improving RA patient outcomes in terms of immune function and symptomatology. While TNF alpha inhibitors are generally beneficial, some studies have demonstrated that TNF alpha inhibitors may increase the risk of adverse cardiovascular events. While this continues to be debated, our study investigates the role of Tumor Necrosis Factor Receptor 1 (TNFR1) and Tumor Necrosis Factor Receptor 2 (TNFR2) in cardiac tissue. TNFR1 is an apoptotic receptor and its inhibition by TNF alpha inhibitors is subsequently cardioprotective. However, TNF alpha inhibitors may be inhibiting TNFR2 receptors even more so than TNFR1 receptors. TNFR2 is primarily a cardioprotective receptor and its greater inhibition results in the cardiovascular morbidity associated with TNF alpha inhibitors.