BUFFALO, NY – December 30, 2024 – A new editorial was published in Oncotarget’s Volume 15 on December 24, 2024, titled “Pitfalls and perils from FDA-approved germ-line cancer predisposition tests.“

In a paper published in Molecular Biomedicine, the authors underscore the heterogeneity of Cancer-associated fibroblasts (CAFs) by elaborating on their origins, types and function. Most importantly, by elucidating the direct or indirect crosstalk between CAFs and immune cells, the extracellular matrix, and cancer cells, they emphasize the tumorigenicity of CAFs in cancer. Finally, they highlight the challenges encountered in the exploration of CAFs and list targeted therapies for CAF, which have implications for clinical treatment.

This study, led by Prof. Bin Du, Li Weng, and Hongda Chen from Peking Union Medical College Hospital, examines the rising burden of sepsis among hospitalized cancer patients in China from 2017 to 2019. Sepsis, a serious condition caused by infection-related inflammation, is a leading cause of death in cancer patients. The study found a 35.3% increase in sepsis incidence, from 4111.20 to 5564.42 per 100,000 admissions. Sepsis-related mortality also rose by 53%, with higher rates in older patients, especially those aged 85 and above. The study highlights the need for focused interventions on infection prevention, early detection, and timely management to reduce sepsis-related mortality, especially in regions with limited healthcare resources.

SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3). Mutations in SETD2 cause human diseases including cancer and developmental defects. In mice, Setd2 is essential for embryonic vascular remodeling. Given that many epigenetic modifiers have recently been found to possess noncatalytic functions, it is unknown whether the major function(s) of Setd2 is dependent on its catalytic activity or not. Here, we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2 (Setd2-CD). We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity, as the Setd2^CD/CD and Setd2^−/− mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns. However, compared with Setd2^−/−, the Setd2^CD/CD mice showed less severe defects in allantois development, and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5′ Hoxa cluster genes in these two models. Collectively, this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.

Human cells contain two types of adenosine deaminases (ADA) each with unique properties: ADA1, which is present in all cells where it modulates intracellular functions and extracellular signaling, and ADA2, which is secreted by immune cells. The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1. ADA2 has distinct characteristics, such as low adenosine affinity, heparin-binding ability, and putative lysosomal entry. Here, we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9 (TLR9) agonists, specifically CpG oligodeoxynucleotides (CpG ODNs). We show that interferon-alpha (IFN-α) is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells (pDCs). Additionally, the pretreatment of pDCs with RNA further stimulates IFN-α secretion by pDCs after activation with CpG ODNs. Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs. In conclusion, decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-α secretion from pDCs, improving immune responses against intracellular infections and cancer.