Oncol Rep. 2026 Mar;55(3):49. doi: 10.3892/or.2026.9054. Epub 2026 Jan 23.

ABSTRACT

Lung cancer remains a significant global health challenge, with metastatic progression being the leading driver of mortality. Organoid technology provides a tractable, physiologically relevant platform to model key aspects of lung cancer metastasis in vitro. The present review summarized methodologies for constructing and interrogating these models, covering tissue sources, culture modalities, gene editing and in vivo transplantation; applications in studying metastatic mechanisms, drug screening and capturing intra‑ and intertumoral heterogeneity are also highlighted. Persistent challenges include standardizing derivation and culture conditions, improving preservation of tumor‑microenvironmental interactions, expanding immune‑competent and vascularized models, and addressing scalability, cost, and regulatory and ethical considerations for clinical translation. Future directions include integrating multi‑omics approaches and spatial profiling, leveraging artificial intelligence for image and response analytics, advancing immune‑organoid models and establishing shared standards, reference materials and reporting guidelines to enhance reproducibility and clinical impact.

PMID:41574717 | DOI:10.3892/or.2026.9054

Clin Transl Oncol. 2026 Jan 21. doi: 10.1007/s12094-025-04214-3. Online ahead of print.

ABSTRACT

Pancreatic cancer (PC), predominantly pancreatic ductal adenocarcinoma, remains one of the most lethal malignancies, largely due to late diagnosis and intrinsic resistance to conventional therapies. In recent years, mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) have emerged as clinically actionable biomarkers in a small but distinct subset of PC, accounting for approximately 1-2% of cases. These tumors display unique molecular characteristics, including a high prevalence of wild-type KRAS and TP53, elevated tumor mutational burden, and recurrent kinase fusions, which together confer enhanced immunogenicity and increased sensitivity to immune checkpoint inhibitors (ICIs). In addition to their therapeutic relevance, dMMR/MSI-H status has important diagnostic implications for the identification of Lynch syndrome-associated pancreatic cancers, informing genetic counseling and familial risk assessment. This review summarizes current understanding of the molecular basis of mismatch repair deficiency and microsatellite instability in PC, evaluates available diagnostic approaches such as immunohistochemistry, polymerase chain reaction, and next-generation sequencing, and discusses the prognostic and predictive significance of dMMR/MSI-H status. Emerging clinical evidence supporting the use of ICIs in selected patients across neoadjuvant, adjuvant, and advanced disease settings is also reviewed, along with challenges related to assay discordance, tumor heterogeneity, and immunotherapy resistance. Finally, future directions are highlighted, emphasizing the need for standardized testing algorithms, integration of multi-omics and spatial profiling technologies, and prospective clinical studies to optimize precision treatment strategies for this rare but clinically meaningful subtype of pancreatic cancer.

PMID:41563663 | DOI:10.1007/s12094-025-04214-3

Gut. 2026 Jan 13:gutjnl-2025-335683. doi: 10.1136/gutjnl-2025-335683. Online ahead of print.

ABSTRACT

BACKGROUND: Accumulating evidence has demonstrated that distinct tumour-promoting and tumour-restraining cancer-associated fibroblast (CAF) subtypes coexist in pancreatic ductal adenocarcinoma.

OBJECTIVE: To develop targeted CAF therapeutic strategies by reprogramming tumour-promoting CAF subtypes.

DESIGN: We leveraged multiomics technologies to systematically identify and characterise CAF subtypes transcriptionally, epigenetically and spatially and correlate them with clinicopathological features.

RESULTS: We found that complement-secreting CAFs (csCAFs), initially identified by our group and inflammatory CAFs (iCAFs) share significant overlap in their transcriptional profiles and chromatin accessibility. iCAFs specifically express transcription factors from the heme and oxidative homeostasis pathway and the activator protein 1 family, which are both involved in cellular response to oxidative stress. Notably, the composition of csCAFs among all CAFs declined during pancreatic carcinogenesis, while trajectory analysis showed that csCAFs could potentially differentiate into iCAFs. Spatially resolved analysis indicated that tumour regions with a higher csCAF composition were associated with lower levels of TGF-β ligands, fewer M2 tumour-associated macrophages and increased levels of lipid mediators. Additionally, we identified a spatially defined CXCL12-CXCR4 ligand-receptor interaction between csCAFs and T cells, but in distinct patterns between different metastatic organs. Patients with a higher composition of csCAFs have significantly longer overall survival and recurrence-free survival through multiplex immunohistochemistry and bulk RNA-seq deconvolution.

CONCLUSION: Our study demonstrates that csCAFs may represent an early-stage iCAF subtype and suggests a promising strategy for reprogramming iCAFs into csCAFs.

PMID:41534892 | DOI:10.1136/gutjnl-2025-335683

Discov Oncol. 2026 Jan 5. doi: 10.1007/s12672-025-04366-2. Online ahead of print.

ABSTRACT

BACKGROUND: Emerging evidence highlights the overexpression of Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) in multiple malignancies. However, its pan-cancer prognostic significance, tumor immune microenvironment (TIME) interactions, and therapeutic implications remain underexplored.

METHODS: Multi-omics data were integrated from UCSC Xena, GTEx, UALCAN, and published cohorts. PCMT1 expression patterns were systematically analyzed across 33 cancer types. Associations between PCMT1 and clinical outcomes, immune infiltration, immune checkpoint genes (ICGs), tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity were evaluated using bioinformatics pipelines.

RESULTS: Our pan-cancer analysis revealed differential expression patterns of PCMT1 across various malignancies, with significant upregulation in 20 cancer types and downregulation in 3 cancer types. Notably, PCMT1 overexpression was predominantly observed in epithelial-origin tumors, such as ACC (adrenocortical carcinoma), BRCA (breast invasive carcinoma), COAD (colon adenocarcinoma), and LUAD (lung adenocarcinoma). Survival analysis demonstrated that elevated PCMT1 expression was significantly correlated with unfavorable prognosis in multiple epithelial tumors, particularly in BRCA, esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LIHC), and mesothelioma (MESO). Furthermore, comprehensive analysis identified significant associations between PCMT1 expression and various tumor microenvironment features, including immune scores, six distinct immune cell types, four immunosuppressive cell populations, cancer-associated fibroblasts (CAFs)-related markers, and immunosuppressive factors. PCMT1 expression also showed significant correlations with tumor mutation burden (TMB), microsatellite instability (MSI), DNA stemness score (DNAss), and RNA stemness score (RNAss). Particularly noteworthy was the strong positive correlation between PCMT1 expression and CAFs infiltration, along with their associated factors. These findings were further validated in independent immunotherapy cohorts, where PCMT1 consistently demonstrated immunosuppressive characteristics.

CONCLUSION: Multi-omics analysis suggests that PCMT1 may serve as a potential prognostic biomarker and a novel immunotherapy target for pan-cancer.

PMID:41491065 | DOI:10.1007/s12672-025-04366-2