bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–09–07
thirteen papers selected by
Sergio Marchini, Humanitas Research



  1. Nature. 2025 Sep 03.
      The spatial resolution of omics analyses is fundamental to understanding tissue biology1-3. The capacity to spatially profile DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation4,5, is lacking. Here we introduce a method for whole-genome spatial co-profiling of DNA methylation and the transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and the postnatal mouse brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The concordance and distinction in spatial patterns of the two modalities highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics that underlie mammalian embryogenesis for both the epigenome and transcriptome, revealing details of sequence-, cell-type- and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to include DNA cytosine methylation, enabling a more comprehensive understanding of tissue biology across development and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09478-x
  2. Cancer Discov. 2025 Sep 04. 15(9): 1774-1776
      Wang and colleagues showed that ctDNA can be detected in plasma up to 3 years prior to clinical diagnosis. The study highlights the need for ultrasensitive and multimodal approaches that integrate the detection of mutations and copy-number changes with advanced computational platforms to deliver effective early-detection strategies. See related article by Wang et al., p. 1794.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1025
  3. Curr Treat Options Oncol. 2025 Sep 05.
       OPINION STATEMENT: Ovarian cancer, particularly high-grade serous carcinoma (HGSC), remains a leading cause of mortality in gynecologic oncology. Emerging research identifies serous tubal intraepithelial carcinoma (STIC) as a precursor lesion in many HGSC cases, highlighting its role in ovarian cancer pathogenesis and prevention. Management of STIC is challenging, as there is only limited data available to guide clinical decision-making. For average-risk women, opportunistic salpingectomy is increasingly being adopted during routine procedures such as hysterectomy or cesarean section. This intervention has demonstrated significant potential in reducing ovarian cancer incidence while maintaining safety and feasibility. For high-risk individuals, particularly BRCA mutation carriers, risk-reducing salpingo-oophorectomy (RRSO) remains the gold standard. RRSO significantly lowers ovarian cancer risk, though alternative approaches like salpingectomy alone or radical fimbriectomy are under investigation to preserve ovarian function in younger patients. To improve STIC detection, SEE-FIM pathology protocol is recommended when patients are undergoing risk-reducing surgery to prevent ovarian cancer, but challenges such as diagnostic variability and limited data persist. When STIC is detected incidentally, management varies based on risk factors and lesion characteristics. Genetic counseling and testing are essential when STIC is identified, as hereditary predisposition may guide further management. Surgical management is advised for cases of STIC with microinvasive carcinoma, but routine use of surgical management for STIC is not clearly defined in the literature. Bilateral oophorectomy is generally recommended when STIC is identified, and adnexal structures have not yet been removed. Chemotherapy is not recommended for treatment of STIC. Surveillance is suggested when STIC has been diagnosed, but there are no set guidelines as to the frequency and type of monitoring. Future directions include refining molecular profiling to predict progression and conducting randomized studies to establish evidence-based guidelines. Multidisciplinary collaboration is essential to optimize prevention and treatment, ultimately reducing HGSC incidence and improving patient outcomes.
    Keywords:  BRCA; High grade serous cancer; Ovarian cancer; Peritoneal cancer; Risk reducing salpingo-oophorectomy; STIC
    DOI:  https://doi.org/10.1007/s11864-025-01346-0
  4. medRxiv. 2025 Aug 28. pii: 2025.08.25.25333715. [Epub ahead of print]
      High-grade serous carcinoma (HGSC) is the most common ovarian cancer subtype, typically diagnosed at late stages with poor prognosis. Understanding early molecular events driving HGSC progression is crucial for timely detection and development of effective treatment strategies. We performed and integrated spatial cell-type resolved proteomics and paired transcriptomics across 25 women with precursor lesions of the fallopian tube and/or HGSC. Epithelial cell signatures revealed early activation of SUMOylation machinery, increased ATR and Wnt signaling, and enhanced MHC-I antigen presentation along the disease trajectory. The stroma exhibited extracellular matrix remodeling and interferon-mediated inflammation. Serous tubal intraepithelial carcinomas (STICs) in cancer patients contained a pro-coagulative signature and reduced APOA1/2 compared to STICs in individuals without cancer. We functionally established important roles of epithelial-derived TRIP13 and SUMOylation, and cancer-associated fibroblast-derived SULF1 and BGN in HGSC progression. These findings provide unique molecular insights into HGSC pathogenesis and identify potential new therapeutic targets for intervention.
    DOI:  https://doi.org/10.1101/2025.08.25.25333715
  5. Immunol Rev. 2025 Sep;334(1): e70059
      Tertiary lymphoid structures (TLSs) are organized aggregates of lymphocytes, myeloid cells, and stromal cells that form at sites of inflammation, providing adaptive immune responses outside of secondary lymphoid organs (SLOs). Found in various pathological conditions-including chronic infections, cancer, organ transplantation, autoimmune diseases, and allergy-the presence of TLSs is linked to potentiation of local immunity. TLSs can be beneficial or detrimental, depending on context, and have been implicated as prognostic for disease severity and therapy response. Architecturally, TLSs resemble SLOs with distinct T and B cell areas supported by fibroblasts that secrete chemokines and cytokines that support immune cells. These structures must be created de novo in non-lymphoid tissues; thus, the steps for TLS formation mimic, but do not completely copy, those of SLO formation. The accumulation of immune cells in tissues in inflammatory settings can initiate remodeling of tissue fibroblasts, leading to TLS formation; this process is common across tissues, although there are tissue- and disease-specific pathways that impact TLS formation in certain contexts. This review will explore the immune-stromal crosstalk in kidney, lung, and skin TLSs across a range of disease settings, highlighting shared as well as tissue-specific mechanisms for TLS formation.
    Keywords:  fibroblast; germinal center; kidney; lung; skin; tertiary lymphoid structure
    DOI:  https://doi.org/10.1111/imr.70059
  6. ACS Omega. 2025 Aug 26. 10(33): 36890-36903
      The early 1990s marked a pivotal era in oncology with the elucidation of the molecular etiology of hereditary cancers, fundamentally transforming our understanding of genetic susceptibility. Ovarian cancer (OC) remains the most fatal gynecologic malignancy, often diagnosed at advanced stages with limited modifiable risk factors. Globally, it ranks as the eighth most frequently diagnosed cancer in women, underscoring its significant public health burden. Hereditary ovarian cancer (HOC), predominantly driven by pathogenic germline mutations in BRCA1 and BRCA2, confers a strikingly increased lifetime risk of OC. These tumor suppressor genes encode proteins essential for homologous recombination-mediated DNA repair, and their dysfunction promotes genomic instability. Risk assessment models, such as BRCAPRO and BOADICEA, facilitate early genetic screening, enabling the implementation of preventive strategies such as risk-reducing salpingo-oophorectomy (RRSO) and chemoprevention with oral contraceptives, both associated with reduced OC incidence. The advent of targeted therapies, particularly PARP inhibitors (olaparib, niraparib, and rucaparib), has revolutionized HOC management, exploiting synthetic lethality in homologous recombination-deficient tumors. These agents significantly improved progression-free survival, establishing them as a cornerstone of precision oncology. This review delineates the evolving landscape of HOC, focusing on pharmacoepidemiology, risk assessment, chemoprevention, and targeted therapy, aiming to refine clinical decision-making and advance precision medicine for improved patient outcomes.
    DOI:  https://doi.org/10.1021/acsomega.5c05260
  7. Small Methods. 2025 Sep 04. e00770
      Despite the availability of numerous approved immunotherapies for various cancers, durable progression-free survival remains relatively uncommon among patients with advanced cancer. As research into immunotherapy intensifies, the heterogeneity and complexity of the tumor microenvironment (TME) have emerged as critical determinants of treatment response and a major obstacle to understanding tumor resistance mechanisms. Recent advances in spatially resolved transcriptomics (SRT) enable transcriptome-wide measurement of gene expression while preserving essential spatial information, which supports the characterization of the features of the TME. This review outlines key challenges in cancer immunotherapy and emphasizes the importance of the TME in determining therapeutic efficacy. SRT strategies suitable is systematically introduced for TME profiling, comparing their relative advantages and limitations. Additionally, bioinformatics tools and methods used to reconstruct spatial tissue patterns are discussed from SRT data. Furthermore, how SRT is explored can enhance the understanding of the complexity and heterogeneity of the TME, facilitate the identification of novel therapeutic targets, and advance biomarker discovery to refine personalized treatment strategies for diverse cancer patients. Finally, future perspectives on the application of SRT in cancer immunotherapy and addressing the associated challenges are provided.
    Keywords:  cancer immunotherapy; spatially resolved transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1002/smtd.202500770
  8. Gynecol Oncol. 2025 Sep 01. pii: S0090-8258(25)00964-3. [Epub ahead of print]201 160-163
      The 15th Biennial Ovarian Cancer Research Symposium presented by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research held on September 20-21, 2024, in Seattle, WA covered cutting-edge research on the etiology and pathobiology of ovarian cancer. Several sessions focused on novel therapies including targeting the immunosuppressive microenvironment and advances in early detection. In this article we provide an overview of the key findings presented in the biology of ovarian cancer session, which covered novel model systems that accurately represent the disease, features of the tumor microenvironment (TME), and advances in understanding the genomic landscape and biomarkers of response.
    Keywords:  Model systems; Ovarian cancer; Treatment resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ygyno.2025.08.014
  9. Cell Rep Med. 2025 Aug 26. pii: S2666-3791(25)00389-1. [Epub ahead of print] 102316
      Ovarian high-grade serous carcinoma (HGSC) is one of the deadliest gynecological malignancies, with 10%-15% of patients exhibiting primary resistance to first-line chemotherapy. To characterize the molecular drivers of chemo-refractoriness, we perform multi-omics profiling of treatment-naive biopsies from patients with refractory HGSC enrolled in the DECIDER observational trial. We demonstrate that chemo-refractory HGSC is characterized by diminished interferon type I (IFN-I) and enhanced hypoxia pathway activity, and baseline IFN-I activity in chemo-naive cancer is an independent prognostic factor. Single-cell RNA sequencing and spatial protein profiling analyses corroborate the importance of elevated IFN-I activity in response to chemotherapy. Importantly, in vitro experiments demonstrate that high levels of IFN-I signaling increase cell chemosensitivity to platinum in a cell-autonomous manner. Together, these findings indicate that the IFN-I pathway activity in HGSC cancer cells predicts response to first-line chemotherapy in HGSC, proposing the stimulation of the IFN-I response as a therapeutic strategy. The study is registered at ClinicalTrials.gov (NCT04846933).
    Keywords:  chemo-refractory cancer; chemoresistance; cyclic immunofluorescence; interferon type I signaling; ovarian cancer; platinum-based chemotherapy; prospective clinical cohort; real-world data; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102316
  10. Int J Gynecol Cancer. 2025 Aug 11. pii: S1048-891X(25)01227-7. [Epub ahead of print]35(10): 102107
       OBJECTIVE: We sought to validate the prognostic utility of comprehensive genomic profiling (CGP)-based molecular stratification for patients with endometrial carcinoma and to assess co-occurring biomarkers across subtypes.
    METHODS: This study included patients from a de-identified nationwide (US-based) endometrial cancer clinicogenomic database who underwent CGP testing as part of routine care. Molecular subtypes were classified as POLE mutated (POLEmut), MSI-H, TP53 mutated (TP53mut), and no specific molecular profile (NSMP). Time to next treatment and overall survival were compared between molecular subtypes, with multivariable Cox models adjusted for relevant covariables.
    RESULTS: Of 1,139 evaluated patients with advanced or recurrent endometrial carcinoma, the prevalence of the 4 molecular subtypes was 1% POLEmut, 22% high microsatellite instability, 47% TP53mut, and 31% NSMP. Compared with NSMP patients, POLEmut patients had numerically more favorable time to next treatment (HR 0.50, 95% CI 0.21 to 1.21) and overall survival (HR 0.52, 95% CI 0.17 to 1.66). High microsatellite instability patients had similar time to next treatment (HR 1.08, 95% CI 0.89 to 1.30) and overall survival (HR 0.91, 95% CI 0.71 to 1.19) relative to NSMP patients. TP53mut patients had the least favorable outcomes for time to next treatment (compared with NSMP, HR 1.39, 95% CI 1.19 to 1.62) and overall survival (HR 2.15, 95% CI 1.77 to 2.61). In multivariable analysis, TP53mut status was associated with less favorable time to next treatment and overall survival. Frequencies of other biomarkers varied by molecular subtype.
    CONCLUSIONS: The Cancer Genome Atlas (TCGA)/Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) molecular classifier for endometrial carcinoma can be recapitulated using CGP and provides prognostic stratification even within an advanced or recurrent disease cohort. CGP for molecular subclassification could support trial design and enrollment and inform treatment escalation or selection.
    Keywords:  CGP; Endometrial; Molecular Classification; Real-World
    DOI:  https://doi.org/10.1016/j.ijgc.2025.102107
  11. MedComm (2020). 2025 Sep;6(9): e70327
      Pleural mesothelioma (PM) presents significant challenges in clinical management, with current treatment options such as chemotherapy, anti-angiogenic therapies, and immunotherapies only modestly extending progression-free survival (PFS) and overall survival (OS). Another relevant reason is the absence of subsequent-line therapy strategies following progression of PM after approved therapy. Despite extensive research efforts, the development of effective targeted therapies has proven difficult, as most identified mutations in PM tend to be tumor suppressors rather than the driving mutations seen in other cancers. This review aims to provide an in-depth analysis of the biological mechanisms of PM, focusing on genetic alterations, the tumor's immune microenvironment, and dysregulated signaling pathways that contribute to tumorigenesis and resistance to treatment. Additionally, we discuss the growing importance of biomarkers for patient stratification and the development of personalized therapeutic approaches tailored to individual molecular profiles. We also explore promising avenues for novel therapeutic strategies, such as combination therapies and immunotherapeutic interventions. By integrating insights from both basic and clinical research, this review seeks to present a comprehensive framework for understanding PM and advancing its therapeutic management, ultimately aiming to improve patient outcomes through more effective and targeted treatment approaches.
    Keywords:  chemoresistance; epigenetic modifications; immunotherapy; pleural mesothelioma; targeted therapy
    DOI:  https://doi.org/10.1002/mco2.70327
  12. Int J Gynaecol Obstet. 2025 Sep;171 Suppl 1 6-35
      In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSCs). Stage IC is now divided into three categories: IC1 (surgical spill), IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface), and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension) and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, including the treatment of ovarian germ cell and stromal malignancies.
    Keywords:  FIGO cancer report; cancer staging; chemotherapy; fallopian tube; ovary; peritoneum
    DOI:  https://doi.org/10.1002/ijgo.70282
  13. Clin Transl Oncol. 2025 Sep 03.
      Endometrial cancer (EC) presents a major global health challenge due to its heterogeneity and complex pathophysiology. The tumor microenvironment (TME), comprising stromal cells, immune cells, endothelial cells, and non-cellular components, critically influences EC progression. Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of EC by revealing TME cellular heterogeneity and interactions. This review synthesizes recent scRNA-seq applications in EC, focusing on two key areas: ① Mapping transcriptional heterogeneity across major cellular components (epithelial, stromal, endothelial, and immune cells); ② Elucidating the factors driving tumor evolution, immune evasion, and differential immunotherapy response. Collectively, these scRNA-seq-derived insights into the dynamic TME ecosystem provide the foundation for translating basic discoveries toward clinical applications. Such advances could thereby promote TME-based personalized therapies and more accurate prognostic predictions.
    Keywords:  Endometrial cancer; Immunotherapy; Intercellular heterogeneity; Prognostic biomarkers; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1007/s12094-025-04032-7