In Cancer Cell this week, a team led by researchers from the US National Institutes of Health describes a method to exploit synthetic lethality to treat the activated B cell-like subtype of diffuse large B cell lymphoma. In studying lenalidomide, an active agent in the disease, the team found that it kills ABC DLBCL cells by augmenting the production of interferon β. "In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and amplify prosurvival NF-κB signaling by transactivating CARD11," the team writes. "Blockade of B cell receptor signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs."
Also in Cancer Cell this week, researchers in Greece report that the inactivation of the tumor suppressor cylindromatosis, or CYLD, in hepatocytes can lead to apoptosis of these cells, inflammation, fibrosis, and liver cancer. CYLD inhibits the NFκB and MAPK activation pathways. In this study, the authors show that liver-specific CYLD disruption triggers hepatocyte cell death, followed by hepatic stellate cell and Kupffer cell activation, and then progressive fibrosis, inflammation, tumor necrosis factor production, and expansion of hepatocyte apoptosis. "At later stages, compensatory proliferation results in the development of cancer foci featuring re-expression of oncofetal hepatic and stem cell-specific genes," the team adds. "The results demonstrate that, in the liver, CYLD acts as an important regulator of hepatocyte homeostasis, protecting cells from spontaneous apoptosis by preventing uncontrolled TAK1 and JNK activation."
Finally in Cancer Cell, researchers in New York report that the production of granulocyte-macrophage colony-stimulating factor induced by oncogenic KRAS promotes the development of pancreatic neoplasia. By analyzing mouse pancreatic ductal epithelial cells, the researchers observed an oncogenic KRASG12D-dependent upregulation of GM-CSF. They also observed enhanced GM-CSF production in human pancreatic intraepithelial neoplasia lesions. "KrasG12D-dependent production of GM-CSF in vivo is required for the recruitment of Gr1+CD11b+ myeloid cells," the team writes. "The suppression of GM-CSF production inhibits the in vivo growth of KrasG12D-PDECs, and, consistent with the role of GM-CSF in Gr1+CD11b+ mobilization, this effect is mediated by CD8+ T cells."