Editors’ Selections from Relevant Scientific Publications

Kupffer cells (Red) interact with hepatic stellate cells and endothelial cells (by Bonnardel Johnny via Wikimedia Commons)A new study reveals that cancer precursors with elevated levels of the transcription factor MEF2D actively remodel the liver microenvironment to promote hepatocellular carcinoma initiation. Using single-cell and spatial transcriptomics analyses, Xiang and colleagues found that MEF2D overexpression triggered epigenetic reprogramming in precursor cells, inducing an oncogenic and secretory phenotype essential for tumor initiation in both murine models and human samples. These precursors activated neuropilin 1 (NRP1) signaling in stem-like Kupffer cells (KC2), driving their differentiation into pro-inflammatory KC1-like cells. The resulting KC1s released cytokines, particularly IL-6, which enhanced an MEF2D-mediated tumor-promoting program in nearby precursors, creating a self-reinforcing inflammatory niche. Importantly, pharmacologic inhibition of NRP1 signaling disrupted KC subtype conversion, reduced inflammation, and significantly suppressed liver tumorigenesis in male mice. These findings highlight a critical mechanism by which precursor cells reprogram the precancerous microenvironment and suggest that targeting KC subtype conversion may be a promising strategy for early cancer prevention.Xiang J, … Qian C. Nat Cancer. 2025 Oct 23.Hormonal contraceptives (from Wellness OBGYN)A nationwide cohort study in Sweden shows that breast cancer risk varies by the formulations of hormonal contraceptives. By analyzing data of over 2 million adolescent girls and premenopausal women followed for 21 million person-years, during which 16,385 breast cancer cases occurred, Hadizadeh and colleagues found that ever use of hormonal contraceptives was associated with increased risk (HR, 1.24; 95% CI, 1.20–1.28). When stratified by type, both combined and progestin-only contraceptives were linked to elevated risk, but progestin-only methods carried a greater relative risk (HR, 1.21; 95% CI, 1.17–1.25) than combined methods (HR, 1.12; 95% CI, 1.07–1.17). Among specific progestins, oral formulations containing desogestrel and implants containing its active metabolite etonogestrel were associated with higher breast cancer risk compared with those containing levonorgestrel. No significant risk increase was observed for medroxyprogesterone acetate injections, etonogestrel vaginal ring, or combined oral drospirenone. These findings indicate that breast cancer risk among hormonal contraceptive users varies by hormone type, providing important information for contraceptive selection.Hadizadeh F, … Johansson Å. JAMA Oncol. 2025 Oct 30:e254480.Progesterone paracrine signaling regulates luminal progenitor cells and fibroblasts (by Simões et al. via Nature)A pilot prevention trial suggested that ulipristal acetate, a progesterone receptor antagonist, significantly reduced markers of breast cancer risk in premenopausal women. In this trial of 24 high-risk participants treated for 12 weeks, Simões and colleagues observed a marked decrease in epithelial proliferation (Ki-67) and a reduction in the proportion, proliferation, and colony-forming ability of luminal progenitor cells that are considered potential cells of origin for aggressive breast cancers. MRI imaging showed decreased fibroglandular volume, while single-cell RNA sequencing, proteomics, histology, and atomic force microscopy revealed remodeling of extracellular matrix, including decreased collagen organization, reduced tissue stiffness and downregulation of key proteins such as collagen VI. In cultured primary human breast epithelial cells, anti-progestin treatment reversed stiffness-induced progenitor activation, linking tissue mechanics to progenitor behavior and cancer risk. These results indicate that progesterone signaling regulates both epithelial and stromal compartments in ways associated with breast cancer risk, supporting the potential of targeting hormone signaling and tissue mechanics as a prevention strategy in high-risk premenopausal women.Simões BM, … Howell SJ. Nature. 2025 Nov 5.PSA test (by Marco Verch via ccnull)A long-term follow-up of the European Randomized Study of Screening for Prostate Cancer evaluated the effect of prostate-specific antigen (PSA) screening on prostate cancer mortality over a median of 23 years. Roobol and colleagues analyzed data from 162,236 men aged 55 to 69 who were randomly assigned, with 72,888 invited to PSA screening and 89,348 assigned to the control group. Over the follow-up period, the screening group had a prostate cancer mortality rate ratio of 0.87 (95% CI, 0.80–0.95) compared with controls, corresponding to an absolute risk reduction of 0.22%, equivalent to preventing one prostate cancer death for every 456 men invited for screening and one for every 12 men diagnosed. However, screening substantially increased prostate cancer diagnoses, particularly low-risk tumors, indicating considerable overdiagnosis. These findings support the potential value of risk-based screening strategies to balance mortality benefits with the harm of overdiagnosis.Roobol MJ, … ERSPC Investigators. N Engl J Med. 2025 Oct 30;393(17):1669–1680.