bioRxiv [Preprint]. 2026 Feb 18:2026.02.18.706515. doi: 10.64898/2026.02.18.706515.

ABSTRACT

The recurrence rate following complete surgical resection of primary non-small cell lung cancer is as high as 55%, yet no approach currently exists to evaluate the risk of local recurrence. The premetastatic paradigm is the recognition that metastasis is preceded by reprogramming naïve tissues to prime a microenvironment for tumor cell survival and subsequent reactivation. Identification of biomarkers of the pre-metastatic niche would allow us to evaluate a patient's risk of local relapse in the normal lung parenchyma surrounding the resected tumor. We designed a workflow incorporating in vivo modelling, radiology, and deep learning-guided three-dimensional (3D) imaging, spatial proteomics, and transcriptomics to identify previously unreported signals associated with the early transformation of the lung parenchyma announcing regional metastasis. We curated biorepository spanning timepoints before and after resection of primary Lewis Lung Carcinoma (LLC) tumors. Using radiology and cellular resolution 3D histology, we calculated the number and distribution of metastases in mouse lungs and developed an algorithm to guide placement of spatial proteomics and transcriptomics to regions containing early micro-metastases and the pre-metastatic microenvironment. Molecular and tissue features associated with presence, size, and location of metastases guided the identification of both myeloid (F4/80) and senescent (p16/p21) cell signatures in the premetastatic and metastatic environments. Finally, multiparametric flow cytometry of metastatic lungs in a senescence reporter GEMM (tdTomato-p16 INKA mice) resolved senescent cells including alveolar macrophages as the cellular phenotypes associated with these early premetastatic signatures. Altogether, this work highlights a novel AI-assisted approach for detection of biomarkers of tissue remodeling during lung cancer invasion.

PMID:41756853 | PMC:PMC12934922 | DOI:10.64898/2026.02.18.706515

Mol Aspects Med. 2026 Feb 23;108:101461. doi: 10.1016/j.mam.2026.101461. Online ahead of print.

ABSTRACT

Diabetes mellitus (DM) is a significant risk factor for several cancers, particularly cancers of the liver, pancreas, and endometrium. This review aims to understand the connections between diabetic pathophysiology and cancer biology. We synthesize how core metabolic disturbances-hyperinsulinemia, hyperglycemia, and inflammation-promote tumorigenesis by dysregulating canonical oncogenic pathways such as IGF-1 signaling, DNA damage repair, and immunometabolism. Subsequently, we focus on how key molecular integrators-such as p38 MAPK, Wnt/β-catenin, and the AGEs-RAGE axis-mediate metabolic stress to confer proliferative and invasive advantages to tumor cells. However, a direct translational application of these mechanisms, particularly in the context of repurposing antidiabetic drugs for cancer therapy, remains challenging due to inconsistent clinical outcomes. To address this gap, we suggest that a fundamental shift in approach is required. We propose that future research must move beyond simple pathway categorization and instead utilize spatial analysis techniques to reveal how diabetic metabolites reshape the tumor microenvironment (TME). By integrating single-cell and spatial omics technologies, the field can begin to map the precise cellular niches within tumors where diabetic metabolites exacerbate malignant progression and foster treatment resistance. This perspective is essential for developing targeted strategies to mitigate cancer risk and improve outcomes for the expanding population of patients with DM and cancer.

PMID:41734405 | DOI:10.1016/j.mam.2026.101461

Future Oncol. 2026 Feb 20:1-14. doi: 10.1080/14796694.2026.2631302. Online ahead of print.

ABSTRACT

Gastric cancer (GC) is an epithelial malignant tumor with high morbidity and mortality. In recent years, more and more studies have strengthened our understanding of how GC develops, including the origin of GC cells, precancerous lesions, gene mutations, transcriptional changes, protein translation and the tumor microenvironment. With the concept of accurate tumor therapy gradually applied to clinical practice, these data provide more reference and basis for early prevention, early screening, early detection and accurate treatment of GC.

PMID:41717787 | DOI:10.1080/14796694.2026.2631302

Oncogene. 2026 Feb 11. doi: 10.1038/s41388-026-03679-y. Online ahead of print.

ABSTRACT

Non-small cell lung cancer (NSCLC) with spinal metastasis represents a clinical challenge due to its aggressive nature, limited treatment options, and profound impact on patient quality of life. Here, we report the development of an innovative upconversion mesoporous silica nanoparticle (UCMS) platform co-loaded with celecoxib and rose bengal (UCMS@CXB/RB), engineered to synergistically combine photodynamic therapy (PDT) and cyclooxygenase-2 (COX-2) inhibition. Upon near-infrared (NIR) irradiation, UCMS@CXB/RB generated abundant reactive oxygen species, triggered immunogenic cell death, and significantly suppressed prostaglandin E2 signaling, leading to reduced angiogenesis and improved antitumor immunity. In vitro and in vivo studies confirmed that this nanoplatform effectively remodeled the tumor microenvironment, inhibited tumor growth, and alleviated cancer-induced spinal dysfunction. Single-cell multi-omics analysis further revealed dynamic crosstalk among immune cells, tumor cells, and endothelial populations, providing mechanistic insights into the multifaceted therapeutic effects of UCMS@CXB/RB. Our results underscore the clinical potential of integrating PDT with targeted COX-2 blockade to address the complex pathophysiology of NSCLC spinal metastasis. This study presents a promising minimally invasive therapeutic strategy with strong translational relevance for managing metastatic NSCLC and improving patient outcomes.

PMID:41673094 | DOI:10.1038/s41388-026-03679-y

Hum Genomics. 2026 Feb 3. doi: 10.1186/s40246-026-00927-w. Online ahead of print.

ABSTRACT

BACKGROUND: Extrachromosomal DNA (ecDNA) is an emerging hallmark of cancer that promotes tumor evolution and heterogeneity. However, the molecular characteristics and clinical significance of ecDNA in hepatocellular carcinoma (HCC) remain incompletely understood.

METHODS: The clinical outcomes, genomics, transcriptomics, proteomics, tumor microenvironment, and drug target landscapes of ecDNA-negative and ecDNA-positive HCC in the Cancer Genome Atlas (TCGA) were compared. Next, the least absolute shrinkage and selection operator (LASSO) and random survival forest (RSF) algorithms were used to screen the ecDNA gene signature. A nomogram was constructed and evaluated based on the risk score and clinicopathological features. Finally, the role of DNASE1L3 was validated through in vitro experiments.

RESULTS: EcDNA-positive tumors showed increased vascular invasion, higher AFP levels, and more TP53 mutations. These tumors displayed unique activation of proliferation pathways, decreased stromal infiltration, and heightened immune activation. Our validated six-gene signature (RNF186, BMP6, AOC1, FBLL1, MYBL2, and DNASE1L3) demonstrated strong prognostic value when combined with tumor stage in the nomogram. Notably, DNASE1L3 was downregulated in HCC, showed endothelial cell-specific expression, and suppressed the proliferation and migration of Hep3B2.1-7 cells.

CONCLUSION: Our study characterizes the molecular and clinical distinctions between ecDNA-negative and ecDNA-positive HCC and establishes a clinically applicable gene signature for patient prognosis. These findings advance our understanding of ecDNA-driven tumor heterogeneity and provide potential strategies for personalized HCC management.

PMID:41634868 | DOI:10.1186/s40246-026-00927-w

Gut. 2026 Jan 30:gutjnl-2025-337247. doi: 10.1136/gutjnl-2025-337247. Online ahead of print.

ABSTRACT

BACKGROUND: Gastric cancer, with disproportionately higher incidence in East Asia, arises from complex host-microbiome-environment interactions beyond Helicobacter pylori (HP) infection. However, the molecular architecture linking environmental carcinogens, microbial succession and host response remains unclear.

OBJECTIVE: To delineate multifactorial aetiologies and clinically actionable subtypes/biomarkers of gastric cancer through integrative proteogenomic, microbial and environmental exposure profiling.

DESIGN: We established a multiomics atlas of paired tumour, adjacent mucosa tissues and blood from 154 treatment-naïve Taiwanese patients, integrating whole-exome sequencing, RNA-seq, proteome and phosphoproteome profiling with carcinogen signatures, HP status, microbiome composition and refined anatomical mapping. Cell-based functional assays tested carcinogen effects. Microbial subtype was assessed in an independent cohort.

RESULTS: A polycyclic-aromatic-hydrocarbon signature, dibenz[a,h]acridine, emerged as a high-risk exposure promoting invasion, immune suppression and poor survival, significantly exceeding nitrosamine-linked risk in this cohort. Multilayer integration defined three initiation ecologies: HP-driven inflammatory, non-HP microbiome-enriched immune-silent and HP-free microbially depleted states. Among HP-negative tumours, a Streptococcus-enriched subtype associated with tight-junction (CLDN18.2/ZO-1/OCLN) disruption and epithelial-mesenchymal transition, whereas a subset of clinically aggressive cases retained CLDN18.2-high epithelial-stable subtype for therapeutic accessibility. An independent cohort revealed gastric juice-derived Streptococcus anginosus abundance inversely correlated with tight-junction proteins. Anatomical mapping reveals location-specific, sex-specific, subtype-specific oncogenic networks and kinase activity, including CDK4 activation in clinical biomarker-negative tumours. Decision-tree models combining exposure and proteome-immune states refined recurrence and survival prediction beyond stage.

CONCLUSION: This proteogenomic framework defines exposure-informed and microbiome-informed gastric cancer subtypes, providing a molecular schema for patient stratification, prevention and actionable therapeutic vulnerabilities.

PMID:41617485 | DOI:10.1136/gutjnl-2025-337247

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