bims-enbcad 2026-01-25 papers

Issue of 2026–01–25
eight papers selected by
Xiao Qin, University of Oxford

Oncol Rep. 2026 Mar;pii: 52. [Epub ahead of print]55(3):

Key immune cells in the tumor immune microenvironment of colorectal cancer: Roles and research advances (Review).

Ming Qiu, Chongyuan Lan, Minglin Lin, Hui Ma.

Colorectal cancer (CRC) is the third most common cancer globally and the second leading cause of cancer‑related mortalities. Surgery‑centered multimodal therapy remains the cornerstone of care, yet outcomes are poor in advanced or drug‑resistant disease. The tumor immune microenvironment (TIME), a network of immune cells, cytokines and stromal elements, shapes antitumor immunity and can either restrain or encourage tumor growth. Specific immune cells within the TIME influence CRC biology, while immune‑checkpoint blockade has delivered notable benefits, especially in microsatellite instability‑high tumors. The present review discusses the principal immune cell populations in the CRC TIME, outlines their mechanisms of action and discusses emerging cell‑based immunotherapies that may guide future precision treatment.

Keywords: colorectal cancer; immune cells; tumor immune microenvironment

DOI: https://doi.org/10.3892/or.2026.9057

Mol Syst Biol. 2026 Jan 19.

Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes.

Viola Hollek, Francisca Böhning, Catalina Florez Vargas, Anja Sieber, Markus Morkel, Nils Blüthgen.

Oncogenic mutations shape colorectal cancer (CRC) biology, yet their impact on transcriptional phenotypes remains incompletely understood, and their individual prognostic value is limited. Here, we perform a pooled single-cell transcriptomic screen of over 100,000 CRC cells with a comprehensive barcoded library of oncogenic variants across genetically diverse CRC lines. Using a variational autoencoder-based interpretable factor model, we identify ten conserved oncogene-driven transcriptional modules (TMOs) representing core cancer phenotypes such as cellular plasticity, inflammatory response, replicative stress, and epithelial-to-mesenchymal transition. Engagement of these modules can be context-dependent, reflecting interactions between oncogene-induced driver pathways and background genetics. TMO activity in patient tumors stratifies CRC cohorts into high- and low-risk groups, improving relapse-free survival prediction beyond existing classification systems. Our study systematically links oncogenic signaling to transcriptional states and clinical outcomes, establishing a functional framework for module-based patient stratification in precision oncology.

Keywords: Colorectal Cancer; Oncogenes; Signatures; Single Cell Screening; Transcriptional Modules

DOI: https://doi.org/10.1038/s44320-025-00186-2

J Gastroenterol Hepatol. 2026 Jan 20.

Novel Liquid Biopsy in Gastrointestinal Cancers.

Li-Chun Chang, Tang-Long Shen, Takahiro Ochiya.

Gastrointestinal (GI) cancers represent a significant global health burden, being among the leading causes of cancer-related deaths. The prognosis for patients remains unsatisfactory, largely because most cancers are detected at advanced stages. Traditional diagnostic methods, such as radiological and histopathological examinations and serum tumor markers like AFP, CEA, CA-125, and CA-199, possess limitations in sensitivity and specificity, particularly for early screening. A major drawback of tissue biopsy is its inability to fully capture the inherent heterogeneity within tumors, as mutations can differ between primary and metastatic sites. In this context, liquid biopsy has emerged as a promising, minimally invasive alternative for detecting cancer-associated materials present in various body fluids. The concept of liquid biopsy, initially centered on circulating tumor cells, has expanded to encompass other critical biomarkers such as circulating tumor DNA, extracellular vesicles, and circulating tumor RNA. Analyzing these biomarkers using advanced techniques like next-generation sequencing or proteomics can unveil a wealth of potential information. Liquid biopsy offers numerous advantages, being less invasive, more convenient, potentially more cost-effective, and providing a dynamic, real-time snapshot of the entire tumor burden that reflects both intertumoral and intratumoral heterogeneity. This review provides an overview of key liquid biopsy biomarkers and their associated detection technologies, discusses their burgeoning clinical applications across various GI cancer types, and highlights the current challenges and future directions in this rapidly evolving field.

Keywords: circulating tumor DNA; circulating tumor cell; extracellular vesicle; gastrointestinal cancer; liquid biopsy

DOI: https://doi.org/10.1111/jgh.70219

bioRxiv. 2025 Dec 02. pii: 2025.11.30.691355. [Epub ahead of print]

SpatialProp: tissue perturbation modeling with spatially resolved single-cell transcriptomics.

Eric D Sun, Alejandro Buendia, Anne Brunet, James Zou.

Perturbational studies are the gold standard for identifying causal relationships between components of biological systems. Recent technological advances, including Perturb-seq and related assays, have enabled high-throughput screening of genetic perturbation effects on single cells. Several machine learning tools have also been developed to infer the effect of single-cell perturbations. However, both approaches are generally limited to dissociated cells, and the effect of genetic perturbations on neighboring cells within intact tissue has not yet been explored. Here we introduce a computational framework using graph neural networks for predicting the effect of multi-gene, multi-cell type perturbations on cells in whole tissue sections. We leverage the natural heterogeneity in tissue microenvironments across spatially resolved single-cell transcriptomics datasets to train SpatialProp (Spatial Propagation of Single-cell Perturbations). We show that SpatialProp can predict gene expression from the tissue microenvironment and map fine-grained steering of tissue microenvironments to new target states. To assess for causal enrichment in spatial perturbation predictions, we propose CausalInteractionBench, a bidirectional benchmarking approach using curated cell-cell interactions. Under this benchmark, we evaluate the causal utility of SpatialProp in predicting the spatial effects of different perturbations. SpatialProp provides a framework towards rapid hypothesis generation and in silico perturbation experiments, particularly in the study of spatially patterned tissue biology.

DOI: https://doi.org/10.64898/2025.11.30.691355

Nat Genet. 2026 Jan 22.

Genomic evolution of pancreatic cancer at single-cell resolution.

Haochen Zhang, Palash Sashittal, Elias-Ramzey Karnoub, Akhil Jakatdar, Shigeaki Umeda, Jungeui Hong, Anne Marie Noronha, Agustin Cardenas, Amanda Erakky, Caitlin A McIntyre, Akimasa Hayashi, Nicolas Lecomte, Marc Hilmi, Wungki Park, Nan Pang, Eileen M O'Reilly, Alice C Wei, Benjamin J Raphael, Christine A Iacobuzio-Donahue.

Most evolutionary studies on pancreatic cancer rely on bulk sequencing, yet clonal evolution happens at the single-cell level. We used single-nucleus DNA sequencing to study 137,491 single nuclei from 24 pancreatic neoplasms reflecting various clinical scenarios. We found higher frequencies of somatic alterations to driver genes that bulk studies indicate; many manifest as copy number alterations and account for the majority of spatial heterogeneity. In pancreatic cancers with canonical KRAS oncogenic mutations, we found likely varied dependence on the genotype that may signify differential response to KRAS inhibition. In pancreatic cancers with germline heterozygous BRCA2 mutations, we discovered varied mechanisms and timing of inactivation of the wild-type allele that sculpted differential evolutionary trajectories. Inactivation of tumor-intrinsic response to transforming growth factor-β happens through various mechanisms, takes place after oncogenesis and coincides with invasion and metastasis, reflecting increasing selective pressure for the phenotype later in pancreatic ductal adenocarcinoma development.

DOI: https://doi.org/10.1038/s41588-025-02468-9

Cancer Discov. 2026 Jan 21. OF1-OF17

Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer.

William C H Cross, Salpie Nowinski, George D Cresswell, Maximilian Mossner, Abhirup Banerjee, Bingxin Lu, Marc J Williams, Georgios Vlachogiannis, Laura J Gay, Ann-Marie Baker, Christopher Kimberley, Frederick J H Whiting, Hayley L Belnoue-Davis, Pierre Martinez, Maria Traki, Viola Walther, Kane Smith, Javier Fernandez-Mateos, Erika Yara-Romero, Erica A Oliveira, Salvatore Milite, Giulio Caravagna, Chela T James, George Elia, Alison Berner, Chang-Ho Ryan Choi, Pradeep Ramagiri, Ritika Chauhan, Nik Matthews, Jamie Murphy, Anthony Antoniou, Susan K Clark, Miriam Mitchison, Jo-Anne Chin Aleong, Enric Domingo, Inmaculada Spiteri, Stuart A C McDonald, Darryl Shibata, Miangela M Laclé, Lai Mun Wang, Morgan Moorghen, Ian P M Tomlinson, Marco Novelli, Marnix Jansen, Alan Watson, Nicola Valeri, Nicholas A Wright, John A Bridgewater, Manuel Rodriguez-Justo, Chris P Barnes, Hemant M Kocher, Simon J Leedham, Andrea Sottoriva, Trevor A Graham.

Aneuploidy is near-ubiquitous in cancer and contributes to tumor biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterized. We performed longitudinal genomic analysis of 755 samples from 167 patients with colorectal-derived neoplasias from different stages through metastasis and treatment. Adenomas had few copy number alterations (CNA) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual colorectal cancer glands from the same tumor had similar karyotypes, despite evidence of ongoing instability at the cell level. CNAs in metastatic lesions, after therapy, and in late recurrences were similar to the primary. Mathematical modeling indicated that these data are consistent with the action of negative selection on CNAs that "trap" cancer genomes on a fitness peak characterized by specific CNAs. Hence, progression to colorectal cancer requires traversing a rugged fitness landscape, whereas subsequent CNA evolution is constrained by negative selection.
SIGNIFICANCE: We profiled 167 long-term responders longitudinally (755 samples), documenting long-term cancer evolution. We found that a genetic bottleneck is required for progression and is associated with dramatic increase in CNAs but decrease in clonal diversity. After initiation, copy number evolution is constrained by negative selection through metastasis and treatment.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0813