bims-tumhet 2026-03-01 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–03–01
nine papers selected by
Sergio Marchini, Humanitas Research

Multimodal tumor-agnostic ctDNA analysis for minimal residual disease detection and risk stratification in ovarian cancer: results from the MITO16a/MaNGO-OV2 trial.
Reconstructing single-cell resolution from spatial transcriptomics with CellRefiner.
Reference materials and external quality assessment for liquid biopsy assays: Expert opinions from the European Liquid Biopsy Society ctDNA workshop.
Initiation of Tertiary Lymphoid Structures for Cancer Immunotherapy.
A Guide for Spatial Omics Technologies: Innovation, Evaluation, and Application.
Clinical Importance of Molecular Biomarkers in Pleural Mesothelioma.
Tertiary lymphoid structures correlate with reduced recurrence risk and enhanced antitumor immunity in esophageal squamous cell carcinoma with pathologic non-complete response to neoadjuvant chemoimmunotherapy.
ESMO Clinical Practice Guideline Express Update on the management of epithelial ovarian cancer.
Integrating liquid biopsy and mutational signatures to advance precision oncology.

ESMO Open. 2026 Feb 25. pii: S2059-7029(26)00029-3. [Epub ahead of print]11(3): 106087

Multimodal tumor-agnostic ctDNA analysis for minimal residual disease detection and risk stratification in ovarian cancer: results from the MITO16a/MaNGO-OV2 trial.

L Paracchini, A Velle, P Di Gennaro, L Mannarino, L Ancona, D Lorusso, S C Cecere, N Colombo, L Beltrame, A Fagotti, G Tasca, M Piemontese, L Arenare, D Califano, F Galdiero, R Zadro, P Chiodini, F Perrone, E Biagioli, M D'Incalci, C Romualdi, S Pignata, S Marchini.

   BACKGROUND: Advanced-stage epithelial ovarian cancer (EOC) remains a therapeutic challenge due to high relapse rates and limited survival, while standard post-surgical parameters such as residual tumor (RT) incompletely capture minimal residual disease (MRD) and offer limited insight into tumor evolution. To address this gap, we investigated whether a multimodal, tumor-agnostic analysis of circulating tumor DNA (ctDNA)-integrating tumor fraction (TF) and genome-wide fragmentomic profiles (PF)-could refine early risk stratification after cytoreductive surgery and enable longitudinal monitoring during therapy.
MATERIALS AND METHODS: A total of 393 plasma samples from 173 patients in the phase IV MITO16a/MaNGO-OV2a trial were analyzed by shallow whole-genome sequencing at three time points: post-surgery/pre-chemotherapy (B1), post-chemotherapy (B2), and at the end of maintenance therapy or upon disease progression during maintenance (B3). Associations with progression-free survival (PFS) and overall survival (OS) were assessed using multivariable Cox models adjusted for clinical covariates.
RESULTS: TF was detectable in 97% of patients at B1, including those classified as optimally debulked, and outperformed established clinical covariates in predicting survival [PFS: hazard ratio (HR) 1.02, P = 0.008; OS: HR 1.04, P = 0.005]. PF provided independent prognostic values (PFS: HR 1.06, P = 0.010; OS: HR 1.10, P = 0.005), and combined TF/PF modeling identified subgroups with distinct survival trajectories beyond clinical predictors (PFS: HR 1.76, P = 0.015; OS: HR 2.06, P = 0.029). Longitudinal copy number profiling revealed dynamic remodeling under treatment pressure, with recurrent 19q13.42 amplification emerging at B2 and B3.
CONCLUSIONS: Together, these findings establish multimodal ctDNA profiling as a sensitive, non-invasive strategy for MRD detection and longitudinal surveillance in advanced EOC, refining prognostic assessment beyond clinical and surgical factors while paving the way for precision-guided therapeutic management.

Keywords:  EOC prognosis; agnostic ctDNA analysis; ctDNA; genome-wide fragmentomic analysis; multimodal analysis; tumor fraction

DOI:  https://doi.org/10.1016/j.esmoop.2026.106087
Nat Commun. 2026 Feb 27.

Reconstructing single-cell resolution from spatial transcriptomics with CellRefiner.

Eric Bourgain-Chang, Xiangyu Kuang, Zixuan Cang, Qing Nie.

Single-cell RNA sequencing technologies profile the transcriptome of individual cells but lack the spatial context necessary for dissecting cellular interactions like cell-cell communications. On the other hand, most current spatial transcriptomic technologies lack cellular resolution, limiting their capability for realistic downstream analysis. Here we present CellRefiner, a physical model-based method that integrates a single-cell dataset with a paired spatial dataset to generate single-cell resolution in the imputed spatial data. CellRefiner models cells as particles connected by forces, and then optimizes cell locations with spatial proximity constraints, gene expression similarity, and ligand-receptor interactions between cells. We systematically benchmark CellRefiner over a variety of simulated and real datasets using Visium, MERFISH, seqFISH, Slide-seqV2, and STARmap datasets to demonstrate its accuracy, robustness, and ability to recover spatial patterns of cells. We also demonstrate its utility for improving spatially dependent analysis over the original spatial data for the contact-based cell-cell communication on mouse cortex and lymph node tissues. Our results show CellRefiner is capable of reconstructing single-cell resolution from non-single-cell resolution spatial data, allowing downstream analysis that requires individual-cell resolution and spatial information.

DOI: https://doi.org/10.1038/s41467-026-70090-2
Cancer Treat Res Commun. 2026 Feb 19. pii: S2468-2942(26)00062-6. [Epub ahead of print]47 101151

Reference materials and external quality assessment for liquid biopsy assays: Expert opinions from the European Liquid Biopsy Society ctDNA workshop.

Zandra C Deans, Jennifer Fairley, Simon J Patton, Claudia Koch, Rodrigo A Toledo, Klaus Pantel, Patrizio Giacomini, Ed Schuuring, Ellen Heitzer, Simon A Joosse.

  The European Liquid Biopsy Society (ELBS) ctDNA Workshop in 2023 brought together 44 experts from various disciplines to discuss the current status and future needs for reference materials and external quality assessment (EQA) in cancer liquid biopsy assays. The workshop focused on identifying, through presentations, discussion, and polls, key aspects that participants considered important for the design and use of reference materials and EQA schemes in ctDNA testing, which is increasingly used to guide crucial treatment decisions in cancer patients. The experts emphasized the importance of using well-characterized reference materials that closely mimic patient-derived ctDNA in terms of biochemical properties and assay performance, including plasma-like reference materials, multiple serial dilutions, and various input amounts to assess analytical sensitivity and specificity. The workshop participants also highlighted the importance of EQA schemes that include a broad range of clinically relevant genetic alterations, low variant allele frequencies, and cover different cancer types. Overall, the outputs of the workshop provide a snapshot of expert opinions with the ELBS community and are intended to inform ongoing discussions on reference materials and EQA for ctDNA testing, to eventually standardize EQA schemes, support improved assay validation, and ensure high-quality clinical reporting when liquid biopsy is used in routine clinical practice.

Keywords:  Expert consensus; External quality assessment; Liquid biopsy testing; Recommendations; Reference material; ctDNA

DOI:  https://doi.org/10.1016/j.ctarc.2026.101151
Research (Wash D C). 2026 ;9 1164

Initiation of Tertiary Lymphoid Structures for Cancer Immunotherapy.

Ji-Yuan Zou, Ze-Tong Li, Ze-Cheng Wang, Hao Li, Zhi-Jun Sun.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates formed by lymphocytes and antigen-presenting cells within chronic inflammatory microenvironments or tumor microenvironments (TMEs), and their initiation phase is a critical step for mounting an effective antitumor immune response. TLS initiation depends on the interplay between lymphoid tissue inducer cells and lymphoid tissue organizer cells and is finely regulated by multiple cytokines and chemokines. This review systematically summarizes the key triggers and signaling networks driving TLS initiation, elucidating how TLSs reshape the TMEs, facilitate antigen presentation, and recruit immune cells to enhance antitumor immune responses. Furthermore, potential strategies to modulate TLS initiation are discussed, along with the emerging role of TLSs as promising targets in cancer immunotherapy.

DOI: https://doi.org/10.34133/research.1164
Adv Sci (Weinh). 2026 Feb 23. e20806

A Guide for Spatial Omics Technologies: Innovation, Evaluation, and Application.

Xiaofeng Wu, Weize Xu, Da Lin, Leqiang Sun, Jinxia Dai, Gang Cao.

  Biological macromolecules assemble into sophisticated spatial architectures to orchestrate fundamental cellular processes. Understanding this architecture is therefore essential for deciphering the mechanisms of life. Driven by advances in high-throughput sequencing and single-molecule imaging, spatial omics technologies have emerged as powerful tools that are revolutionizing biomedical research. This review systematically evaluates current spatial omics methodologies by comparing their key performance parameters. We critically assess their optimal applications and discuss strategies to overcome prevailing challenges in spatial resolution, capture efficiency, robustness, data analysis, and clinical translation. Furthermore, we highlight how these technologies provide unique insights into tissue heterogeneity, cell-cell interactions, developmental dynamics, microenvironmental composition, and neuroanatomy. Our analysis offers guidance for selecting appropriate spatial omics approaches and outlines promising directions for future technological innovation and expanded biomedical applications.

Keywords:  NGS‐based; imaging‐based; multi‐modal; multi‐omics; spatial omics

DOI:  https://doi.org/10.1002/advs.202520806
Cancers (Basel). 2026 Feb 19. pii: 679. [Epub ahead of print]18(4):

Clinical Importance of Molecular Biomarkers in Pleural Mesothelioma.

Logan Roof, Kenna Koehler, Claire Verschraegen.

  Pleural mesothelioma (PM) is a rare malignancy with opportunities for improvement in current treatment paradigms despite recent advances in systemic therapy. While histology remains the most clinically relevant prognostic indicator, the expanding use of immunotherapy and ongoing clinical trials involving targeted therapies have increased interest in the development of predictive and prognostic biomarkers in this disease. This review summarizes the current biologic and therapeutic landscape of PM and the biomarkers that influence prognosis and treatment response. Biomarkers such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) demonstrate inconsistent predictive value in PM and are not currently used in clinical decision pathways in the real-world setting. This review highlights the developing role of dynamic biomarkers such as circulating tumor DNA (ctDNA) for molecular response assessment and minimal residual disease (MRD) detection. This review also examines important genomic and transcriptomic alterations in PM, such as MTAP, BAP1, CDKN2A, and NF2/YAP/TEAD. These alterations provide potential targets for ongoing early-phase clinical trials. Future advances in PM will depend on the development and integration of comprehensive biomarker models that combine clinicopathologic, immune, and molecular features of this complex and heterogenous disease.

Keywords:  immunotherapy; pleural mesothelioma; precision medicine; predictive biomarkers; prognostic biomarkers

DOI:  https://doi.org/10.3390/cancers18040679
Exp Hematol Oncol. 2026 Feb 25. pii: 29. [Epub ahead of print]15(1):

Tertiary lymphoid structures correlate with reduced recurrence risk and enhanced antitumor immunity in esophageal squamous cell carcinoma with pathologic non-complete response to neoadjuvant chemoimmunotherapy.

Yang Wo, Tong Lu, Zijiang Yang, Xiongfei Li, Zheyi Wang, Yizhou Peng, Xuxia Shen, Feng Hou, Wenjie Jiao, Yihua Sun.

   BACKGROUND: The majority of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoimmunotherapy (nCIT) failed to achieve pathologic complete response (pCR), had high risk of postoperative recurrence and lacked prognostic biomarkers. Tertiary lymphoid structures (TLS) are organized aggregates of immune cells and have the potential to regulate antitumor immune response. This study aimed to investigate the prognostic value and immune profile of TLS in non-pCR ESCC.
METHODS: We first analyzed clinicopathological features, recurrence events, and survival outcomes according to TLS status. Subsequently, based on the single-cell sequencing data, we analyzed the differences in the infiltration level, functional status and interaction mode of immune cells based on TLS status. The expression pattern of signature genes and the spatial localization of key immune cell subsets were verified through bulk RNA sequencing and multiplex immunohistochemistry.
RESULTS: The TLS(+) group demonstrated a lower likelihood of postoperative recurrence and superior survival rates relative to the TLS(-) group. The key immune cell subsets responsive to immunotherapy were enriched in the TLS(+) group, and the immune cells in the TLS(+) group showed a functional state of high activation and low exhaustion. Multiplex immunohistochemistry and cell-cell communication analysis suggested that tumor reactive T cells were spatially colocalized with B cells and antigen presenting cells in TLS and exhibited high interaction potential. In the TLS(+) group, we also identified precursor exhausted T cells and long-lived plasma cells with tumor reactivity and matured affinity. The presence of TLS correlated with enhanced synergistic interaction, activation and maturation of immune cells, suggesting a potential role in shaping in situ antitumor immunity.
CONCLUSIONS: TLS status was the independent predictor of postoperative recurrence in non-pCR ESCC. TLS status correlated with the composition, functional state, and interaction patterns of immune cells. Specialized immune niches existed in non-pCR ESCC with TLS, potentially contributing to antitumor immune responses.

Keywords:  Esophageal squamous cell carcinoma; Immune microenvironment; Immunotherapy; Tertiary lymphoid structures

DOI:  https://doi.org/10.1186/s40164-026-00748-6
ESMO Open. 2026 Feb;pii: S2059-7029(25)01902-7. [Epub ahead of print]11(2): 106032

ESMO Clinical Practice Guideline Express Update on the management of epithelial ovarian cancer.

ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org



Keywords:  epithelial ovarian cancer; first-line maintenance rucaparib; guideline; mirvetuximab soravtansine (MIRV); platinum-resistant

DOI:  https://doi.org/10.1016/j.esmoop.2025.106032
NPJ Precis Oncol. 2026 Feb 23.

Integrating liquid biopsy and mutational signatures to advance precision oncology.

Raquel Carrasco, Kristian Dreij.

The effective application of precision oncology in solid tumors remains challenging due to genetic heterogeneity and the absence of actionable alterations in some cancers. In this review, we discuss the integration of liquid biopsy and mutational signatures as a potential framework to address these limitations by enabling longitudinal detection of mutational processes that arise during tumor development and evolution. Together, these complementary approaches hold substantial promise for enhancing cancer screening, refining diagnosis, and guiding personalized therapeutic strategies, thereby advancing the field of precision oncology.

DOI: https://doi.org/10.1038/s41698-026-01337-w