bims-tumhet 2025-09-14 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2025–09–14
twelve papers selected by
Sergio Marchini, Humanitas Research

DNA Methylation in Ovarian and Endometrial Cancers: Predictive and Mechanistic Roles in PARP Inhibitor and ICI Response.
Clinical applications of cell-free DNA-based liquid biopsy analysis.
DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.
Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection.
Integrated spatial transcriptomic profiling to dissect the cellular characteristics of tumor-associated tertiary lymphoid structures.
Spatial multi-omics technologies and applications in cancer.
Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses.
ctDNA detects residual disease after neoadjuvant chemoradiotherapy and guides adjuvant therapy in esophageal squamous cell carcinoma.
Taming cancer evolution surprises.
Tertiary Lymphoid Structures in Human Melanoma: Molecular Mechanisms and Therapeutic Opportunities.
Liquid Biopsy's Role in Head and Neck Tumors: Changing Paradigms in the Era of Precision Medicine.
Past, present and future of drug conjugates for cancer therapy.

Cancer Sci. 2025 Sep 12.

DNA Methylation in Ovarian and Endometrial Cancers: Predictive and Mechanistic Roles in PARP Inhibitor and ICI Response.

Shuhei Kitamura, Ayumi Taguchi, Kana Tamai, Yoko Yamamoto, Anh Quynh Duong, Daisuke Yoshimoto, Ayako Mori, Aya Ishizaka, Saki Tsuchimochi, Kenbun Sone, Masahito Kawazu, Katsutoshi Oda, Yasushi Hirota.

  Cancer treatment is shifting from an organ-based approach to one driven by biological phenotypes, emphasizing the need to understand molecular mechanisms. DNA methylation plays a pivotal role in tumor biology, not only through gene silencing but also by inducing distinct behaviors beyond genetic mutations. In gynecologic cancers, molecular diagnostics, such as homologous recombination deficiency status guiding poly(ADP-ribose) polymerase (PARP) inhibitor therapy in ovarian cancer and deficient mismatch repair/microsatellite instability-high status informing immune checkpoint inhibitor (ICI) therapy in endometrial cancer have already been used in clinical practice. However, tumors with epigenetically driven functional deficiencies, such as BRCA1 promoter methylation in homologous recombination-deficient ovarian cancers or MLH1 promoter methylation in deficient mismatch repair/microsatellite instability-high endometrial cancers, often exhibit poorer prognoses and reduced therapeutic responses compared to their genetically mutated counterparts. Given the unique impact of DNA methylation, precise detection is crucial. Integrating methylation analysis into molecular classification could refine diagnostics-both by identifying mechanistic contributors to treatment response and by serving as predictive biomarkers for therapy selection-thereby optimizing patient management. This review explores the role of DNA methylation in modulating responses to PARP inhibitors and ICIs, highlights its promise as a biomarker in precision oncology, and outlines current developments and clinical challenges in BRCA1 and MLH1 methylation assays.

Keywords:   BRCA1 ; MLH1 ; DNA methylation; PARP inhibitors; immune checkpoint inhibitors

DOI:  https://doi.org/10.1111/cas.70189
Transl Oncol. 2025 Sep 05. pii: S1936-5233(25)00250-5. [Epub ahead of print]61 102519

Clinical applications of cell-free DNA-based liquid biopsy analysis.

Shu Yazaki, Momoko Tokura, Hisaki Aiba, Yuki Kojima, Kouya Shiraishi.

  Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA) from patient blood, have emerged as crucial and minimally invasive adjuncts to standard tissue-based testing. ctDNA testing enables the identification of actionable mutations for targeted therapy and can be routinely used when tissue samples are unavailable for genotyping. Compared to tissue-based testing, ctDNA testing has the advantages of capturing spatial or temporal genomic heterogeneity and facilitating repeated assessments. The utility of liquid biopsies extends to multiple clinical applications, including cancer diagnosis, treatment monitoring, and minimal residual disease (MRD) detection. Numerous clinical trials are currently evaluating treatment strategies using ctDNA testing. In particular, the implementation of adjuvant treatment escalation or de-escalation based on MRD detection could dramatically transform future approaches to solid tumor treatment. Various ctDNA assays have been developed, and it is important to understand their strengths and weaknesses for effective clinical applications. Furthermore, ctDNA testing faces several technical challenges, including low sensitivity in detecting copy number alterations and fusions, as well as the possibility of detecting mutations associated with clonal hematopoiesis of indeterminate potential. In this review, we comprehensively discuss the methodologies and recent advancements in cfDNA-based liquid biopsies for cancer patients, covering diagnosis, genomic profiling, and treatment monitoring. Furthermore, we explore clinical trial designs employing ctDNA testing and anticipate forthcoming changes in patient care.

Keywords:  Cell-free DNA; Circulating tumor DNA; Liquid biopsy; Minimal residual disease; Treatment monitoring

DOI:  https://doi.org/10.1016/j.tranon.2025.102519
Nat Genet. 2025 Sep;57(9): 2226-2237

DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.

TRACERx Consortium

Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients.

DOI: https://doi.org/10.1038/s41588-025-02307-x
Cell Rep Methods. 2025 Jul 21. pii: S2667-2375(25)00119-5. [Epub ahead of print]5(7): 101083

Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection.

Yunze Wang, Yuying Hou, Zhankun Xiong, Libo Lu, Zhanxiang Zong, Bo Wang, Hebing Chen, Wen Zhang, Xionghui Zhou.

  We introduce a cell-free DNA (cfDNA) fragmentation pattern: the fragment dispersity index (FDI), which integrates information on the distribution of cfDNA fragment ends with the variation in fragment coverage, enabling precise characterization of chromatin accessibility in specific regions. The FDI shows a strong correlation with chromatin accessibility and gene expression, and regions with high FDI are enriched in active regulatory elements. Using whole-genome cfDNA data from five datasets, we developed and validated the FDI-oncology model, which demonstrates robust performance in early cancer diagnosis, subtyping, and prognosis. Case studies reveal that key cancer genes such as HER2 and TP53 exhibit significantly different FDIs between cancer and control samples. Simulation experiments suggest that deep targeted sequencing of a small number of regions can achieve high diagnostic efficiency.

Keywords:  CP: cancer biology; CP: systems biology; cancer early detection; cfDNA; liquid biopsy; machine learning

DOI:  https://doi.org/10.1016/j.crmeth.2025.101083
Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01021-6. [Epub ahead of print]44(9): 116250

Integrated spatial transcriptomic profiling to dissect the cellular characteristics of tumor-associated tertiary lymphoid structures.

Xiangjie Li, Xiaojing Chu, Wenbin Xu, Yi Yang, Ting Wei, Yufei Bo, Yuhui Miao, Yu Zhang, Jinyu Wang, Teng Wang, Guohui Dang, Lu Qi, Dan Tong, Linnan Zhu, Hong Zhao, Zemin Zhang, Sijin Cheng.

  The presence and maturation of tumor-associated tertiary lymphoid structures (TA-TLSs) significantly influence immune activation and clinical outcome. We integrated spatial transcriptomics data across 23 cancers to construct a pan-cancer TA-TLS atlas, revealing cellular dynamics and spatial organization under different maturation states. We revealed a preferential enrichment of IgG+ plasma cells in mature TLSs, and both in silico and in vitro analyses consistently revealed that the identified CCL19+ perivascular cells may act as lymphoid tissue organizer cells associated with TA-TLS formation. Additionally, we observed the presence of arterial endothelial cells within TA-TLSs, which could acquire high endothelial venule-like phenotypes in response to Notch signaling inhibition, with enhanced immune recruiting capacity. Our results provide a comprehensive cellular dissection of TA-TLSs and shed light on the mechanisms of TA-TLS formation and maturation, which hold promise in prioritizing therapeutic strategies targeting TLS, with the potential to transform poor prognostic tumors into immunogenic tumors.

Keywords:  CCL19+ perivascular cell; CP: Cancer; CP: Immunology; IgG+ plasma cells; high endothelial venule; lymphoid tissue organizer; spatial transcriptomics; tumor-associated tertiary lymphoid structures

DOI:  https://doi.org/10.1016/j.celrep.2025.116250
Biosystems. 2025 Sep 09. pii: S0303-2647(25)00186-8. [Epub ahead of print] 105576

Spatial multi-omics technologies and applications in cancer.

Lulin Ji.

  Spatial multi-omics integrates individual genomics technologies with a single technology that simultaneously acquires data from multiple genomics, enabling parallel or even identical tissue sections for joint analysis of cells in tissues. It facilitates the analysis of cell-cell-interactions and provides a three-dimensional panoramic view of tissues. Thus, joint profiling of spatial multi-omics features may enable us to reconstruct key processes in tumorigenesis. Through spatial multi-omics technology, researchers have revealed spatial cellular interactions, TLS identification, changes in immune function, and established a spatial map of human tumors and a spatial gene database, which facilitates the development of personalized tumor therapy. In the future, there may be a need to further develop new spatial analysis techniques and tools, mainly in terms of spatial and temporal resolution, throughput, and sensitivity, to aid in cancer diagnosis and treatment and to decode novel mechanisms of tumorigenesis and development. In this review, we provide guidance for selecting appropriate spatial multi-omics techniques by elucidating the advantages and disadvantages of various spatial multi-omics and highlight advances in cancer field of spatial multi-omics technologies.

Keywords:  Immune; Precise medicine; Spatial metabolomics; Spatial proteomics; Spatial transcriptomics; Tumor

DOI:  https://doi.org/10.1016/j.biosystems.2025.105576
Nat Med. 2025 Sep 08.

Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses.

Joshua E Reuss, Paul K Lee, Reza J Mehran, Chen Hu, Suqi Ke, Amna Jamali, Mimi Najjar, Noushin Niknafs, Jaime Wehr, Ezgi Oner, Qiong Meng, Gavin Pereira, Samira Hosseini-Nami, Mark Sausen, Marianna Zahurak, Richard J Battafarano, Russell K Hales, Joseph Friedberg, Boris Sepesi, Julie S Deutsch, Tricia Cottrell, Janis Taube, Peter B Illei, Kellie N Smith, Drew M Pardoll, Anne S Tsao, Julie R Brahmer, Valsamo Anagnostou, Patrick M Forde.

Immune checkpoint blockade (ICB) is standard of care in advanced diffuse pleural mesothelioma (DPM), but its role in the perioperative management of DPM is unclear. In tandem, circulating tumor DNA (ctDNA) ultra-sensitive residual disease detection has shown promise in providing a molecular readout of ICB efficacy across resectable cancers. This phase 2 trial investigated neoadjuvant nivolumab and nivolumab/ipilimumab in resectable DPM along with tumor-informed liquid biopsy residual disease assessments. Patients with resectable epithelioid/biphasic DPM enrolled sequentially to nivolumab 240 mg every 2 weeks (q2w) for three cycles (Arm A, n = 16) or nivolumab 3 mg kg-1 q2w for three cycles plus ipilimumab 1 mg kg-1 on cycle 1 (Arm B, n = 14), followed by surgery, optional chemotherapy and/or radiotherapy, and nivolumab 480 mg q4w for 1 year. Co-primary endpoints included safety and feasibility; key exploratory endpoints included progression-free survival (PFS), overall survival (OS) and ctDNA analyses. The trial met its primary endpoints, and, in Arms A and B, 81.3% and 85.7% of patients proceeded to surgery, respectively. Treatment was safe, with a single dose-limiting toxicity in each arm. In Arm A, median PFS and OS were 9.6 months (95% confidence interval (CI): 2.5-27.7) and 19.3 months (95% CI: 14.9-34.7), respectively. In Arm B, median PFS and OS were 19.8 months (7.1-not reached) and 28.6 months (20.4-not reached), respectively. Persistent ctDNA was detected during neoadjuvant therapy in patients who did not undergo complete surgical resection due to disease progression (Fisher's exact test, P = 0.00013). Patients with detectable ctDNA on cycle 3 and pre-surgery had shorter PFS (log-rank test, P = 0.027 and P = 0.0059, respectively); this association was more pronounced when quantitative ctDNA changes were considered (log-rank test, P = 1.8 × 10-6). Our findings support the feasibility of neoadjuvant ICB and the clinical utility of ctDNA analyses to capture residual disease in resectable DPM. ClinicalTrials.gov identifier: NCT03918252 .

DOI: https://doi.org/10.1038/s41591-025-03958-3
Cell Rep Med. 2025 Aug 29. pii: S2666-3791(25)00407-0. [Epub ahead of print] 102334

ctDNA detects residual disease after neoadjuvant chemoradiotherapy and guides adjuvant therapy in esophageal squamous cell carcinoma.

Zhichao Liu, Guoqiang Wang, Yang Yang, Yuchen Su, Hong Zhang, Jun Liu, Peng Cui, Xuning Fan, Jinyu Yang, Zhihong Zhang, Xing Gao, Yinkai Chao, Bianca Mostert, J Jan B van Lanschot, Bas P L Wijnhoven, Simon Law, Chunguang Li, Shangli Cai, Zhigang Li.

  The diagnostic accuracy of circulating tumor DNA (ctDNA) for detecting molecular residual disease (MRD) after multimodal treatment remains unclear. In a prospective cohort of 132 patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoradiotherapy (nCRT) followed by clinical response evaluation and surgery, tumor-informed personalized-panel and fixed-panel ctDNA assays are applied to serial blood samples. Personalized ctDNA assay demonstrates a superior baseline detection rate (99.2%) and outperforms fixed panels in diagnosing post-nCRT residual disease. Integrating personalized ctDNA with conventional clinical diagnostic methods increases sensitivity for predicting non-pathological complete response (non-pCR) from 78.4%-80.7% to 92.0%-93.2%. Patients with detectable MRD post-nCRT and/or post-surgery exhibit worse survival outcomes. In non-pCR patients, adjuvant immunotherapy improves disease-free survival in post-surgery MRD-positive cases, whereas MRD-negative patients derive no benefit. These findings support incorporating ctDNA into response assessment to guide organ-sparing strategies and adjuvant therapy decisions in ESCC. This study is registered at ClinicalTrials.gov (NCT03937362).

Keywords:  adjuvant immunotherapy; circulating tumor DNA; esophageal squamous cell carcinoma; molecular residual disease; neoadjuvant chemoradiotherapy; organ preservation

DOI:  https://doi.org/10.1016/j.xcrm.2025.102334
Nat Methods. 2025 Sep 10.

Taming cancer evolution surprises.

Vivien Marx.

DOI: https://doi.org/10.1038/s41592-025-02802-3
Cells. 2025 Sep 04. pii: 1378. [Epub ahead of print]14(17):

Tertiary Lymphoid Structures in Human Melanoma: Molecular Mechanisms and Therapeutic Opportunities.

Gelare Ghajar-Rahimi, Ishika Patel, Nabiha Yusuf.

  Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates often found in chronic inflammatory conditions, including cancer. These structures, which share many cellular and functional features with secondary lymphoid organs, can profoundly influence the tumor microenvironment by promoting local anti-tumor immune activation. TLSs have been observed in various cancers, including melanoma, and are associated with improved responses to immunotherapy and clinical outcomes. However, our understanding of the molecular mechanisms underlying TLS formation and function remains incomplete. This review summarizes the current findings on TLSs in human melanoma, drawing from multiple studies to provide an updated overview. We discuss the cellular composition, spatial distribution, and genetic signatures of TLSs at different stages of melanoma pathogenesis and in subtypes including acral, uveal, and desmoplastic melanoma. Additionally, we examine the influence of tumor mutational burden (TMB) and complement activation on TLS formation, as well as the role of TLSs in immune checkpoint inhibitor therapy. We also highlight the potential of TLSs as indicators for disease progression and treatment response, and review preclinical strategies aimed at inducing TLSs to improve therapeutic outcomes. This synthesis aims to support ongoing research into the role of TLSs in melanoma immunobiology.

Keywords:  acral melanoma; desmoplastic melanoma; immune checkpoint inhibitors; immunotherapy; melanoma; tertiary lymphoid structures; uveal melanoma

DOI:  https://doi.org/10.3390/cells14171378
Diagnostics (Basel). 2025 Sep 07. pii: 2262. [Epub ahead of print]15(17):

Liquid Biopsy's Role in Head and Neck Tumors: Changing Paradigms in the Era of Precision Medicine.

Rudy N Zalzal, Najla Fakhruddin, Rami Mahfouz.

  In the era of precision medicine, liquid biopsy has become an indispensable tool in research and clinical diagnostics. This innovative molecular approach offers significant benefits in managing cancers, such as melanoma, colorectal cancer, lung cancer, and, now, head and neck tumors. By addressing the challenges posed by tumor heterogeneity, liquid biopsy aligns seamlessly with precision medicine strategies, providing more accessible methods to detect and monitor genetic alterations in tumors. While biomarkers for head and neck tumors have been identified, integrating these markers into diagnostic workflows remains a challenge due to the complexities of current sampling techniques. Could liquid biopsy pave the way for a breakthrough in the diagnosis, monitoring, and treatment of patients with head and neck cancer? This review explores the expanding role of liquid biopsy in oncology, with a focus on its potential to revolutionize the management of head and neck malignancies. Liquid biopsy has become an integral part of diagnosis, classification, and prognostication of numerous cancers, namely, head and neck tumors. Liquid biopsy should work in concert with histological testing, imaging, surgery, and other diagnostic and therapeutic approaches, as each offers distinct advantages that together contribute to achieving the best possible patient outcomes.

Keywords:  biopsy; head; impact; liquid; neck; tumors

DOI:  https://doi.org/10.3390/diagnostics15172262
Nat Cancer. 2025 Sep 11.

Past, present and future of drug conjugates for cancer therapy.

S Cazzamalli, E Puca, D Neri.

Drug conjugates have emerged as promising tumor-targeted cytotoxics with an improved therapeutic index compared to classical chemotherapeutics. Although traditionally based on antibody ligands, high-throughput screening methods, such as peptide display and DNA-encoded chemical libraries, have enabled the isolation of ultra-high-affinity small ligands and the generation of drug conjugates with better tumor-targeting performance. This Perspective examines the history, major clinical milestones and future of drug conjugates for cancer treatment. We also discuss a new wave of combination modalities, linker strategies, and the development of conjugates based on large and small delivery vehicles.

DOI: https://doi.org/10.1038/s43018-025-01042-w