Cancer Res. 2026 Feb 9. doi: 10.1158/0008-5472.CAN-25-2854. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) exhibit poor clinical outcomes. Metabolic reprogramming of both cancer cells and immune compartments plays a crucial role in shaping the anti-tumor immune response in PDAC. DM-induced metabolic alteration may disrupt the intricate crosstalk between immune cells and tumor-associated immune factors, profoundly influencing PDAC progression. Here, we performed an integrated, spatially resolved multi-omics study to investigate DM-associated, cell-specific metabolic remodeling within the PDAC tumor microenvironment. DM influenced interactions between tumor cells and immune cells, which accelerated PDAC growth in both humans and mice. PDAC patients with DM exhibited higher tumor-stage, poorer differentiation, and worse outcomes. Spatial metabolic and transcriptional profiling revealed that SREBP2-dependent cholesterol biosynthesis exacerbated PDAC progression. Increased cholesterol biosynthesis promoted neutrophil recruitment and accelerated formation of neutrophil extracellular traps (NETs) by stimulating the CXCL1-CXCR1/CXCR2 signaling axis, ultimately promoting PDAC growth. Inhibition of SREBP2, pharmacological blockade of CXCL1, or perturbation of NETs markedly reduced PDAC growth in diabetic mouse models. Together, these multi-omics analyses and follow-up mechanistic studies constitute an integrated approach that elucidates a metabolic mechanism by which diabetes promotes PDAC development by remodeling the tumor immune microenvironment and highlights a potential therapeutic strategy for PDAC with DM.

PMID:41661642 | DOI:10.1158/0008-5472.CAN-25-2854

Mol Med Rep. 2026 Jan;33(1):6. doi: 10.3892/mmr.2025.13716. Epub 2025 Oct 17.

ABSTRACT

R‑loops, three‑stranded nucleic acid structures composed of an RNA:DNA hybrid and displaced single‑stranded DNA, have emerged as important regulators of gene expression and genome maintenance. Although physiological R‑loops participate in normal cellular processes, their dysregulation can threaten genomic integrity by inducing DNA damage and replication stress. The present review explores the role of R‑loops in hepatocellular carcinoma (HCC), a malignancy characterized by marked genomic instability. In the present review, the formation mechanisms of R‑loops, their dual functions in transcriptional regulation and DNA damage, and their specific implications for HCC pathophysiology were discussed. HCC cells exhibit altered R‑loop homeostasis with aberrant accumulation linked to hepatitis B virus infection, inflammatory signaling and oncogene activation. The present review highlighted how HCC cells exploit or manage R‑loops to promote tumor progression, particularly through the epigenetic silencing of differentiation genes and modulation of replication stress responses. Furthermore, emerging therapeutic strategies targeting R‑loop biology were examined, including small molecules that induce synthetic lethality, gene‑based interventions and combination approaches that exploit R‑loop vulnerabilities. Challenges in targeting R‑loops and future directions, including multi‑omics profiling and biomarker development, were also addressed. Understanding the complex interplay between R‑loops and HCC offers promising avenues for novel diagnostic and therapeutic approaches for this malignancy.

PMID:41104860 | DOI:10.3892/mmr.2025.13716

Cell. 2025 Aug 22:S0092-8674(25)00922-5. doi: 10.1016/j.cell.2025.08.008. Online ahead of print.

ABSTRACT

Performing total RNA profiling on formalin-fixed, paraffin-embedded (FFPE) samples, the predominant sample conservation method in clinical practice, remains challenging for current spatial transcriptomics techniques. Here, we introduce Stereo-seq V2, which employs random primers to capture and sequence RNAs in situ on FFPE sections and provides single-cell resolution. The random-priming-based strategy offers unbiased transcript capturing and uniform gene body coverage, which increase the sensitivity to marker genes, the efficiency of non-polyadenylation (poly(A)) RNA profiling, and immune repertoire coverage. We demonstrated the robust performance of Stereo-seq V2 on clinical FFPE samples using triple-negative breast cancer (TNBC) sections and identified tumor-specific alternative splicing events. In a Mycobacterium tuberculosis (Mtb)-infected mouse model, we monitored gene expression dynamics of host and pathogen transcriptomes simultaneously by utilizing Stereo-seq V2. We also assembled immune repertoires and identified Mtb-specific BCR clones, which could also be observed in human tuberculous lung samples. These results highlight Stereo-seq V2's potential in biomedical research and personalized medicine.

PMID:40882628 | DOI:10.1016/j.cell.2025.08.008