Maharaj MSN, Mertens-Walker I, Lisle JE
… +5 more, Herington A, Stephens C, Chai M, Meutermans W, Stephenson SA
Br J Cancer
· 2026 Jul · PMID 41986660
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BACKGROUND: The receptor tyrosine kinase EphB4 is frequently overexpressed in epithelial cancers, including prostate cancer (PCa). SUMOylation is a post-translational modification that influences protein interactions, lo...BACKGROUND: The receptor tyrosine kinase EphB4 is frequently overexpressed in epithelial cancers, including prostate cancer (PCa). SUMOylation is a post-translational modification that influences protein interactions, localisation and stability. This study investigated how SUMOylation regulates EphB4 localisation, stability and function in PCa. METHODS: EphB4 SUMOylation was analysed in PCa cell lines and its contribution to stability assessed using siRNA or chemical inhibition of SUMOylation. An EphB4 mutant protein (K616R) was expressed in PCa cells and proteasomal inhibition was used to assess its stability. Cell migration was measured using a scratch wound assay. Immunoprecipitation was used to determine if mutant EphB4 could be SUMOylated on other residues. RESULTS: EphB4 in PCa cells is constitutively modified by SUMO2/3 and acquires SUMO1 modification when stimulated with ephrin-B2 ligand. SUMOylation of K616 is critical for EphB4 stability. K616R EphB4 protein is degraded by the proteasome, and this is associated with reduced MYC protein and slower migration. Immunoprecipitation revealed that additional SUMOylated lysines may also contribute to EphB4 function. CONCLUSIONS: SUMOylation at K616 stabilises EphB4, promotes MYC signalling and PCa cell migration. These findings identify a novel mechanism regulating EphB4 and highlight SUMOylation as a potential target in EphB4-driven cancers.
Xie X, Lee J, Gi YJ
… +6 more, Poullikkas T, Fuson JA, Fan PD, Fukui JA, Tripathy D, Ueno NT
Br J Cancer
· 2026 Jul · PMID 41986659
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BACKGROUND: Endocrine resistance remains a major challenge in hormone receptor-positive (HR+) breast cancer (BC), where up to 70% of tumours overexpress HER3, a receptor associated with poor prognosis and therapeutic res...BACKGROUND: Endocrine resistance remains a major challenge in hormone receptor-positive (HR+) breast cancer (BC), where up to 70% of tumours overexpress HER3, a receptor associated with poor prognosis and therapeutic resistance. HER3-DXd (patritumab deruxtecan) is currently under clinical investigation for HER3-expressing metastatic BC. However, strategies to further enhance its efficacy, particularly in endocrine therapy-resistant settings, are urgently needed. We hypothesised that targeting ATR, a key regulator of DNA damage repair (DDR), potentiates HER3-DXd in HER3+/HR+ BC, including tamoxifen-resistant (TMR) disease. METHODS: Synergistic partners for HER3-DXd were identified by whole-genome RNAi screening. Treatments' effects on cell cycle, DNA damage, and protein expression were analysed using flow cytometry, comet assay, and Western blotting, respectively. Treatments' antitumor efficacy was assessed using xenograft mouse models. TCGA and CPTAC databases were analysed for clinical relevance. RESULTS: HER3-DXd inhibited growth in both parental and TMR MCF7 and T47D cells. Compared to monotherapies, combining HER3-DXd with an ATR inhibitor enhanced DNA damage, sub-G1 arrest, apoptosis, downregulation of DDR and cell cycle regulatory proteins, and tumour growth inhibition. TCGA and CPTAC analyses confirmed high HER3 expression and correlation of ATR, CHEK1, and TOP1 gene expression with poor prognosis in HR+ BC. CONCLUSION: Combining HER3-DXd with an ATR inhibitor could benefit HER3+/HR+ BC patients with both endocrine-sensitive and -resistant diseases.
Wang Y, Song J, Song S
… +4 more, Zheng S, Li Y, Zhang L, Wang S
Br J Cancer
· 2026 Jul · PMID 41981140
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BACKGROUND: The molecular interplay between Notch and TGF-β signaling in colorectal cancer (CRC) metastasis remains poorly understood. METHODS: Genetic ablation of RBP-J, the central transcriptional mediator of Notch sig...BACKGROUND: The molecular interplay between Notch and TGF-β signaling in colorectal cancer (CRC) metastasis remains poorly understood. METHODS: Genetic ablation of RBP-J, the central transcriptional mediator of Notch signaling, was performed in CRC cells. In vitro functional assays assessed migration, invasion, and transendothelial migration. Metastatic colonization was evaluated in vivo using orthotopic, intrasplenic, and intravenous murine models. Whole-transcriptome analysis, chromatin immunoprecipitation sequencing (ChIP-seq), and luciferase reporter assays were used to analyze RBP-J-mediated transcriptional regulation of SMAD2/SMAD3. Rescue experiments reconstituted SMAD2/SMAD3 in RBP-J knockout (KO) cells to verify functional necessity. RESULTS: RBP-J knockout profoundly impaired CRC cell migration, invasion, and transendothelial migration in vitro, and suppressed metastatic colonization across multiple in vivo models. Transcriptomic and ChIP-seq analyses revealed RBP-J directly binds to SMAD2 and SMAD3 promoters and activates their transcription. Reconstitution of SMAD2/SMAD3 restored the migratory and metastatic capacities of RBP-J KO cells. Mechanistically, Notch signaling primes TGF-β responsiveness by maintaining SMAD2/SMAD3 expression and phosphorylation, establishing a feedforward loop essential for metastasis. CONCLUSION: Notch signaling orchestrates TGF-β-driven metastasis through direct transcriptional control of SMAD2/SMAD3, defining a hierarchical regulatory axis. This offers novel therapeutic targets for metastatic CRC.
Geng R, Cai H, Ji X
… +14 more, Shen X, Wang Z, Li Z, Liu R, Zhang Z, Wang D, Yin Z, Zou J, Guo R, Dai P, Quan Z, Chen L, Ke N, Liu J
Br J Cancer
· 2026 Jul · PMID 41981139
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis and is easy to developing drug resistance to conventional therapies due to its distinctive tumour microenvironment....BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis and is easy to developing drug resistance to conventional therapies due to its distinctive tumour microenvironment. Recent advancements have brought attention to the aberrant copper metabolism in this malignancy, but the influence of intracellular cuproplasia and balance on the tumoral immune microenvironment is still uncertain. METHODS: We analysed copper concentrations and CTR1 expression in PDAC tissues and cell lines. Spatial transcriptomics was employed to delineate the relationship between CTR1 overexpression and tumour-associated neutrophils (TANs) infiltration. Chemokine arrays and molecular assays were used to identify key signalling pathways involved. Functional experiments, including CTR1 knockdown and TRAF6 overexpression, were conducted to assess its impact on neutrophil infiltration and therapeutic synergy with gemcitabine. RESULTS: We identified that CTR1 overexpression drives intracellular copper overaccumulation, activating TRAF6-dependent phosphorylation of JAK/STAT3. Phosphorylated STAT3 transcriptionally upregulates the chemokine CCL2, fostering CCR2-mediated TANs infiltration, which correlates with poor prognosis. Crucially, single-cell RNA sequencing revealed CTR1 knockdown suppresses a pro-metastatic TAN subpopulation (TAN-2) and dramatically reduces TANs recruitment in orthotopic tumour models. This copper-targeted intervention concurrently enhances cytotoxic CD8 effector T cells within the TME. The translational impact is underscored in gemcitabine-resistant PDAC, where hyperactive CTR1 and intensified TANs infiltration create a therapy-refractory condition. Combining CTR1 inhibition with gemcitabine synergistically overcomes this resistance by dual remodelling of the TME. CONCLUSIONS: Our findings shed light on how intracellular copper metabolism-regulating molecules modulate the neutrophil infiltration through the TRAF6/STAT3/CCL2 pathway, and particularly, targeting the copper regulator shows potential in optimising the tumour microenvironment in the treatment of pancreatic cancers. Schematic diagram of the mechanism by which CTR1 regulates neutrophil recruitment through CCL2 transcriptional activation through the TRAF6/JAK/STAT3 Pathway.
Papathanasiou T, Chen X, Carreno F
… +6 more, McKeown A, Roy-Ghanta S, Eccersley L, Kasinathan R, Patel N, Ferron-Brady G
Br J Cancer
· 2026 Jul · PMID 41975042
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BACKGROUND: Belantamab mafodotin, bortezomib and dexamethasone (BVd) demonstrated clinical activity in the phase I/II DREAMM-6 (Arm B) study and significant clinical benefit in the phase III DREAMM-7 study for patients w...BACKGROUND: Belantamab mafodotin, bortezomib and dexamethasone (BVd) demonstrated clinical activity in the phase I/II DREAMM-6 (Arm B) study and significant clinical benefit in the phase III DREAMM-7 study for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy. METHODS: Population pharmacokinetic-derived Cycle 1 (C1) belantamab mafodotin exposures were used to evaluate exposure-efficacy/exposure-safety relationships across multiple doses and schedules for benefit-risk assessment. RESULTS: Belantamab mafodotin C1 exposure was positively associated with response endpoints and grade ≥2/ ≥3 ophthalmic exam findings (OEFs), but not grade ≥2/ ≥3 ocular adverse events (oAEs) or best-corrected visual acuity (BCVA) worsening to 20/50 or worse in both eyes. Probability of very good partial response or better (≥VGPR) was higher than grade ≥3 oAEs/BCVA worsening in both eyes across C1 exposures; efficacy improved at higher C1 exposures without increased OEF risk. Model-based benefit-risk assessment showed a belantamab mafodotin starting dose of 1.9 mg/kg instead of 2.5 mg/kg would result in lower probability of ≥VGPR without reduction in BCVA worsening in both eyes/grade ≥3 oAEs. CONCLUSIONS: An initial belantamab mafodotin dose of 2.5 mg/kg for BVd yields deeper responses with minimal change in safety outcomes versus 1.9 mg/kg for patients with RRMM.
Stepanyan A, Kotsafti A, Rosato A
… +4 more, Castagliuolo I, Scarpa M, Scarpa M, IMMUNOREACT Study Group
Br J Cancer
· 2026 Jul · PMID 41975041
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BACKGROUND: The gut microbiome is increasingly recognized as a modulator of cancer therapy outcomes and a potential predictive biomarker. This systematic review synthesizes current evidence on microbial biomarkers associ...BACKGROUND: The gut microbiome is increasingly recognized as a modulator of cancer therapy outcomes and a potential predictive biomarker. This systematic review synthesizes current evidence on microbial biomarkers associated with neoadjuvant treatment (NT) response in rectal cancer (RC). METHODS: PubMed, Embase, and Ovid Medline databases were searched through March 2025. Eligible studies included RC patients treated with NT with baseline microbial analysis stratified by treatment response. Two reviewers independently performed screening, data extraction, and quality assessment (NIH and STORMS tools). Due to substantial heterogeneity, a structured qualitative synthesis without meta-analysis was conducted following SWiM guidelines, using a direction-of-effect vote-counting approach. RESULTS: Sixteen observational studies (842 patients) were included, covering chemoradiotherapy (nCRT), total neoadjuvant therapy, chemotherapy, and immunochemoradiotherapy. Microbiota composition was investigated by 16S rRNA sequencing, metagenomics, or metatranscriptomics on fecal or tissue samples. While microbial diversity showed inconsistent associations, specific taxa -notably Bacteroides, Fusobacterium and Akkermansia- emerged as recurrent biomarkers of poor response to nCRT. Twelve predictive models reported AUROC values from 0.73 to 0.97, with limited external validation. CONCLUSIONS: Specific microbial taxa show a consistent association with nCRT resistance across independent cohorts. However, methodological heterogeneity and limited reproducibility warrant standardized prospective validation before clinical implementation. PROSPERO: CRD42023433704.
Ellis LB, Bowden SJ, Paraskevaidi M
… +5 more, Lyons D, Paraskevaidis E, Moscicki AB, Flanagan JM, Kyrgiou M
Br J Cancer
· 2026 Jul · PMID 41965938
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BACKGROUND: DNA methylation has been proposed as a predictive biomarker. Cervical intraepithelial neoplasia grade 2 (CIN2) was historically the cut-off for surgical treatment, however it is increasingly managed with acti...BACKGROUND: DNA methylation has been proposed as a predictive biomarker. Cervical intraepithelial neoplasia grade 2 (CIN2) was historically the cut-off for surgical treatment, however it is increasingly managed with active surveillance, while there is currently no accurate way to predict which lesions will regress. METHODS: We performed the first Illumina 850k array on DNA from serial liquid based-cytology cervical samples from young women with CIN2 that were managed with active surveillance (n = 58). Linear regression identified differentially-methylated sites at baseline distinguishing regressors from non-regressors with persistent or progressive disease at 24-months. Associations with imminent regression and histological change were also evaluated. RESULTS: We identified three novel differentially-methylated sites; cg12754953 (ALDH9A1) methylation was significantly increased at baseline in non-regressors, cg18887759 (MED25) methylation was significantly lower in samples from women who regressed within the subsequent 12 months, and cg13556949 (TULP2) methylation increased over time between baseline and 12-months of follow-up in non-regressors as compared to regressors. CONCLUSION: Methylation could help guide treatment decisions in women considering active surveillance of CIN2 lesions. ALDH9A1, MED25 and TULP2 may be implicated as genes with possible roles in host response to viral mechanisms. Larger prospective studies are needed to validate these findings.
Askar B, Heaton S, Barr T
… +10 more, Baugh R, Alzamel N, McConnell S, Jennings VA, Volpato M, Ralph C, Jain M, Kelly RJ, Parrish C, Errington-Mais F
Br J Cancer
· 2026 Jul · PMID 41963598
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BACKGROUND: Approximately 3000 adult patients are diagnosed with AML in the UK each year. Current intensive treatments are not well-tolerated by elderly patients, and the 5-year survival rate is only 5-15%, highlighting...BACKGROUND: Approximately 3000 adult patients are diagnosed with AML in the UK each year. Current intensive treatments are not well-tolerated by elderly patients, and the 5-year survival rate is only 5-15%, highlighting the need for novel and effective therapies. Oncolytic viruses (OVs) preferentially replicate in cancer cells, resulting in direct oncolysis and induction of innate and adaptive anti-tumour immunity. Unfortunately, the efficacy of OVs remains relatively unexplored in AML. METHODS: Using human AML cell lines, healthy-donor peripheral blood mononuclear cells (PBMC) and AML patient samples, we investigated whether combination with clinically applicable apoptotic modulators (SMAC/BH3 mimetics) can potentiate OV-induced cytokine-mediated killing. RESULTS: We confirmed that OVs stimulate PBMCs to produce inflammatory cytokines, which can induce AML cell death. Bystander cytokine-mediated killing was also significantly enhanced in combination with SMAC/BH3 mimetics, with the optimal combination partner varying with AML subtype. We identified interferon (IFN)-α and tumour necrosis factor (TNF)-α as potential mediators of AML cytotoxicity, and SMAC/BH3 mimetics enhanced AML cell death following direct OV infection, indicating autocrine-paracrine signalling events. Pivotally, we confirmed that apoptotic modulators were effective in combination with both Live- and UV-inactivated virus. CONCLUSION: This work has identified a novel reovirus-based combination-immunotherapy for the treatment of AML.
Sarich P, Canfell K, Egger S
… +7 more, Banks E, Joshy G, Wellard-Cole L, Hughes C, Houssami N, Grogan P, Weber MF
Br J Cancer
· 2026 Jul · PMID 41963597
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BACKGROUND: The Australian alcohol health guidelines were revised in 2020 to recommend a maximum of 10 drinks/week. We calculated estimates of cancer caused by alcohol use in Australia for the updated recommended limits....BACKGROUND: The Australian alcohol health guidelines were revised in 2020 to recommend a maximum of 10 drinks/week. We calculated estimates of cancer caused by alcohol use in Australia for the updated recommended limits. METHODS: Cox regression models were used to estimate hazard ratios (HR) for cancer incidence in relation to self-reported alcohol consumption (drinks/week) among 225,805 participants aged ≥45 years (2005-2009) in the New South Wales (NSW) 45 and Up Study, an Australian prospective cohort study (baseline n = 267,357). Cumulative absolute risk of cancer to age 85 years was estimated using 0 to <1 drink/week as the comparator. Population attributable fractions were calculated using Australian national alcohol consumption and cancer incidence data, compared to a theoretical minimum risk exposure of no alcohol consumption. Cancer cases and deaths were ascertained through record linkage to the NSW Cancer Registry and NSW Registry of Births Deaths & Marriages to 2019. Participants diagnosed with cancer pre-baseline were excluded. RESULTS: Over a median 11.4 years, 34,860 cancer cases were recorded. When modelled as a continuous variable, alcohol-related cancer risk increased by 19% for every ten drinks/week increase in consumption (HR: 1.19; 95% confidence interval: 1.15-1.23). By age 85 years, those who consumed >10 drinks/week had an estimated 4.9% higher cumulative absolute risk of an alcohol-related cancer compared to those consuming 0 to <1 drink/week. An estimated 7804 cancer cases (4.6% of all cancer cases) were attributable to alcohol use in 2024. CONCLUSIONS: The proportion of alcohol-attributable cancers in Australia is substantial and somewhat higher than previously estimated.
Michael A, Huynh J, Sutton K
… +6 more, Chow MC, Ford E, Mansi J, Selby P, Skene S, Armes J
Br J Cancer
· 2026 Jun · PMID 41963596
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BACKGROUND: Frail patients with cancer (Ca) have worse survival. Current methods of assessment of fitness (performance status) for cancer treatment, such as chemotherapy, are time -consuming and often not used by practic...BACKGROUND: Frail patients with cancer (Ca) have worse survival. Current methods of assessment of fitness (performance status) for cancer treatment, such as chemotherapy, are time -consuming and often not used by practicing oncologists. The electronic frailty index (SCARF) is derived from a cumulative deficit frailty model and provides a measure of frailty alongside pre-existing conditions. We used this methodology to investigate whether it can predict outcomes of chemotherapy in patients with Ca. METHODS: The study conducted data analysis of Ca patients treated with chemotherapy in England, years 2015-2018; stage II-III breast Ca, stage III colon Ca and stage IIIB-IV non-small-cell lung Ca. The data was linked with hospital admissions to calculate 30-day chemotherapy mortality, overall survival and SCARF. RESULTS: The SCARF was calculated for 78,799 patients. The risk of dying within 30 days of chemotherapy in severely frail patients with colorectal cancer ≥70 y.o. was twice that of the <70 y.o. (OR 2.04 -95% CI 1.58-2.64, mild frailty 1.07-95% CI 0.78-1.45); and 6 times higher in breast cancer (OR 5.73-95% CI 2.66-12.32, mild frailty OR 1.45 95% CI 0.78-2.71). CONCLUSION: The SCARF index predicts poor outcomes from SACT, particularly in breast and colon cancer, and it requires further evaluation.
Br J Cancer
· 2026 Jul · PMID 41963595
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BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with few biomarkers to inform treatment selection or patient prognosis. Methylation profiles of plasma circulating tumour DNA (...BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with few biomarkers to inform treatment selection or patient prognosis. Methylation profiles of plasma circulating tumour DNA (ctDNA) accurately reflect tumour methylomes and may reveal novel biomarkers of mCRPC. METHODS: To establish a novel mCRPC-associated methylation signature for detection of ctDNA, we performed plasma methylome profiling on 27 mCRPC patients and 10 controls (cohort 1). Signature-based ctDNA detection was evaluated across prostate cancer (PC) disease stages using an internal cohort of 93 PC patients and 8 controls (cohort 2), and an external cohort of 115 PC patients (cohort 3). RESULTS: We established a 48-region methylation signature (cfMeCaP) capable of highly sensitive detection of ctDNA in mCRPC (100%, 84% and 95% in cohorts 1, 2 and 3, respectively). cfMeCaP methylation at mCRPC diagnosis was associated with poor progression-free survival (PFS) and overall survival in all three cohorts (p < 0.005), independent of routine clinical variables. Persistent serial detection of ctDNA using cfMeCaP was strongly associated with rapid mCRPC treatment failure (median PFS 4.4 vs. 65.5 months; p < 0.0001), while no detection predicted continued treatment response. CONCLUSION: These results highlight cfMeCaP as a promising non-invasive biomarker for prognostication in mCRPC.
Steffensen JH, Schou LK, Jakobsen AV
… +3 more, Kirchheiner K, Kronborg CJS, Spindler KG
Br J Cancer
· 2026 Jun · PMID 41957141
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BACKGROUND: Despite high survival after radiotherapy (RT) for anal cancer (AC), its impact on female sexual dysfunction (FSD) and vaginal toxicity remains poorly defined. METHODS: We systematically searched MEDLINE, EMBA...BACKGROUND: Despite high survival after radiotherapy (RT) for anal cancer (AC), its impact on female sexual dysfunction (FSD) and vaginal toxicity remains poorly defined. METHODS: We systematically searched MEDLINE, EMBASE, CENTRAL, and CINAHL for studies on women treated with curative-intent RT for anal cancer, addressing prevalence, risk factors, and interventions. Eligibility criteria were defined a priori; prevalence was restricted to studies using modern techniques (IMRT/VMAT), whereas studies of risk factors and interventions were included regardless of modality. Data were extracted using a Cochrane-adapted form, and risk of bias assessed with AXIS. Due to heterogeneity, evidence was synthesized using a narrative approach. RESULTS: Of 3764 records, 32 reported prevalence estimates, 23 examined risk factors, and 8 evaluated interventions. FSD prevalence ranged from 0.9 to 85%. Dyspareunia (0.3-79%), vaginal stenosis (1-88%), and dryness (up to 98%) were frequent and persistent. Higher vaginal doses were associated with worse outcomes, though thresholds varied. Intervention evidence was limited: two studies linked dilator use to less stenosis, and nurse-led or multidisciplinary programs showed promise. CONCLUSIONS: FSD is a prevalent, long-term consequence of RT for AC. This review provides symptom-specific evidence for patient counseling. It underscores the need for standardized assessment, dose optimization, and integrated follow-up strategies for female AC survivors. REGISTRATION: PROSPERO CRD42024592088.
Tipple E, Slay E, Tsigkou O
… +2 more, Choudhury A, Gough J
Br J Cancer
· 2026 Jun · PMID 41957140
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Recent advances in the field of biomaterials show promise in developing pre-clinical models that could elucidate new and innovative treatments for cancer. Both cellular and acellular components can drive cancer formation...Recent advances in the field of biomaterials show promise in developing pre-clinical models that could elucidate new and innovative treatments for cancer. Both cellular and acellular components can drive cancer formation, progression, and metastasis. Biomaterial-based 3D in vitro models can mimic both these cellular and acellular components. Highly tuneable and biocompatible materials such as hydrogels provide a scaffold for in vitro investigations, mimicking the tumour extracellular matrix structure, upon which cancer cells and additional cellular components can be seeded. Such models have already shown good mimicry of the tumour microenvironment, demonstrating a platform that can be used for drug screening, investigation of treatment response, and a model for the mechanisms of cancer progression. The limitations of current preclinical models include long development times, false-positive drug screening results in 2D cell culture models, and high cost of animal models. This review aims to show the role of biomaterial-based models in addressing existing clinical problems by bridging the gap between current research outcomes and their potential clinical impact.
Lindner ES, Admard J, Demidov G
… +13 more, Armeanu-Ebinger S, Sinnberg T, Niessner H, Amaral T, Garbe C, Forschner A, Kelemen O, Hilke FJ, Bonzheim I, Röcken M, Rieß O, Ossowski S, Schroeder C
Br J Cancer
· 2026 Jun · PMID 41957139
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BACKGROUND: While adjuvant therapies are currently recommended for patients with stage IIB-IV melanoma, biomarkers are missing to improve risk stratification to select the most efficient treatment and patients to be incl...BACKGROUND: While adjuvant therapies are currently recommended for patients with stage IIB-IV melanoma, biomarkers are missing to improve risk stratification to select the most efficient treatment and patients to be included in clinical trials. We genetically characterized a large cohort of patients with stage-II-melanoma to identify predictive and prognostic biomarkers. METHODS: Clinical data of 193 stage-II-melanoma patients from the German Central Malignant Melanoma Registry were identified. All patients were therapy-naïve at the time of primary resection and received no adjuvant treatment until recurrence. Tumour-normal pairs were sequenced with a comprehensive cancer panel. RESULTS: 30.1% of the tumours were classified as BRAF-mutated, 28.0% as RAS-, 18.1% as NF1-, and 23.8% as Triple-WT. In-silico prediction identified a potential new candidate driver, CBL, in 10.4% of the patients. GISTIC nominated deletions of region 11q23.1-3 containing CBL as a potential driver alteration. Enrichment of mutations in CBL was replicated in published cohorts. Patients with RAS-mutated tumours and CBL deletions showed worse OS (p = 0.004) and RFS (p = 0.044). Point mutations in CBL were highly enriched in patients with NF1-mutated tumours, showing a trend (p = 0.18) towards worse OS. CONCLUSIONS: Our findings suggest CBL as a novel driver gene in melanoma, which is mutated in a relevant fraction of patients. Deletions of 11q23.1-3 including CBL were identified as a prognostic marker indicating a higher risk of recurrence and shorter survival. Furthermore, CBL could support patient stratification to identify high-risk patients who may benefit from adjuvant therapies or intensified monitoring strategies.
Wang Z, Ingebriktsen LM, Bekkhus T
… +13 more, Ma L, Queiro-Palou A, Shi W, Bazioti A, Panagias MA, Vigorelli M, Lehrstrand JH, Ring S, Dimberg A, Wik E, Hoivik EA, Fuxe J, Ulvmar MH
Br J Cancer
· 2026 Jun · PMID 41957138
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BACKGROUND: Lymphatic metastasis is strongly associated with poor prognosis. Although the chemokine receptor CCR7 is a well-established promoter of lymphatic dissemination, its prognostic relevance remains weak. We show...BACKGROUND: Lymphatic metastasis is strongly associated with poor prognosis. Although the chemokine receptor CCR7 is a well-established promoter of lymphatic dissemination, its prognostic relevance remains weak. We show that tumour cell plasticity, defined by podoplanin (PDPN)-expression and promoted by hypoxia, intersects with CCR7 function in triple-negative breast cancer (TNBC). METHODS: In vivo and in vitro studies using a CCR7-expressing TNBC mouse model were combined with transcriptomic profiling. Human relevance was assessed using scRNA-seq datasets from cell lines and primary tumours, as well as METABRIC breast cancer cohorts. RESULTS: A PDPN-defined tumour cell mesenchymal shift, promoted by hypoxia, was required for efficient CCR7-driven lymphatic metastasis and tumour progression. PDPN-expression was linked to tumour cell collagen-expression and suppression of interferon-signalling, features associated with an immune-cold microenvironment. PDPN-expression with effects on interferon and collagen programmes was observed across murine and human TNBC cell lines and correlated with hypoxia signatures in primary TNBC, mirroring murine findings. In METABRIC, a high combined CCR7-PDPN score predicted poor survival in lymph node-positive patients, whereas either marker alone lacked prognostic value. CONCLUSIONS: PDPN is a tumour cell-associated biomarker of plasticity in TNBC, revealing synergy between hypoxia-induced mesenchymal phenotypic shifts and CCR7 in promoting lymphatic dissemination and poor prognosis.
Sun S, Ma G, Cheng L
… +9 more, Zhang H, Fan G, Wu L, Zhang X, Xue F, Fu T, Ji X, Wan Q, Liu Y
Br J Cancer
· 2026 Jun · PMID 41957137
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BACKGROUND: The extracellular matrix (ECM) plays a pivotal role in lung adenocarcinoma (LUAD) progression and chemoresistance, yet its regulatory mechanisms remain incompletely understood. Here, we identify ZNF514 as a n...BACKGROUND: The extracellular matrix (ECM) plays a pivotal role in lung adenocarcinoma (LUAD) progression and chemoresistance, yet its regulatory mechanisms remain incompletely understood. Here, we identify ZNF514 as a novel tumour suppressor that critically governs ECM remodelling. METHODS: To elucidate the role of ZNF514 in LUAD, we employed a multi-platform approach integrating LUAD organoids, tumour specimens, xenograft mouse models, and cancer cell lines. Transcriptomic profiling was performed to assess ZNF514 expression and its clinical prognostic relevance. Mechanistically, chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay and pathway enrichment analyses identified ZNF514 as a transcriptional repressor of collagen-encoding genes. RESULTS: Analyses of LUAD clinical tissues, patient-derived organoids, and The Cancer Genome Atlas (TCGA) datasets revealed a significant downregulation of ZNF514, which correlated with poor prognosis. Functionally, ZNF514 overexpression suppressed organoid formation, subcutaneous tumour growth, and cellular migration and invasion, while enhancing cisplatin (DDP) sensitivity. Mechanistically, RNA sequencing, ChIP assay and dual-luciferase reporter assays identified COL1A1 as a direct transcriptional target of ZNF514. ZNF514 directly binds to the COL1A1 promoter and represses its transcription, thereby contributing, at least in part, to altered extracellular matrix (ECM) remodelling and attenuation of COL1A1-associated epithelial-mesenchymal transition (EMT) in LUAD models. CONCLUSIONS: Together, these findings identify ZNF514 as a tumour-suppressive transcription factor that inhibits LUAD proliferation, invasion, and migration and enhances cisplatin sensitivity, at least in part, through transcriptional repression of COL1A1 and modulation of ECM remodelling.
Nazzani S, Silvani C, Saitta C
… +19 more, Macchi A, Torelli T, Stagni S, Gallo G, Bonacina E, Marmiroli A, Bernasconi V, Claps M, Giannatempo P, Cascella T, Lanocita R, Barella M, Paolini B, Colecchia M, Tesone A, Catanzaro MA, Biasoni D, Montanari E, Nicolai N
Br J Cancer
· 2026 Jun · PMID 41957136
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BACKGROUND: The role of post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) in non-seminomatous germ cell tumour (NSGCT) patients with persistently elevated serum tumour markers remains controversial, alth...BACKGROUND: The role of post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) in non-seminomatous germ cell tumour (NSGCT) patients with persistently elevated serum tumour markers remains controversial, although traditional management favours salvage chemotherapy. This study aimed to re-define the surgical and oncologic outcomes of salvage PC-RPLND. METHODS: We select 107 (2008-2023) consecutive NSGCT patients undergoing PC-RPLND with elevated markers after ≥1 chemotherapy line. Multivariable linear regression models (MLRM), and Cox proportional hazards models recurrence-free survival (RFS) and overall survival (OS) were used. RESULTS: Definitive histology revealed viable GCT (47.7%), post-pubertal teratoma (32.7%), fibro-necrotic tissue (FNT) (11.4%), and somatic malignancy (8.4%). After a median follow-up of 45 months, overall 5-year RFS was 54% and OS was 68%. Outcomes varied significantly by histology: post-pubertal teratoma had superior 5-year OS (96%) and RFS (77%), while somatic malignancy and FNT predicted worse RFS (MCRM HRs 23.11 and 28.77, respectively). Larger residual mass size correlated with higher relapse risk and increased probability of somatic malignancy. Advanced stage and increasing chemotherapy lines also associated with poorer outcomes. CONCLUSIONS: Salvage PC-RPLND for marker-positive NSGCT achieved meaningful survival, particularly for patients with post-pubertal teratoma. These findings support surgery, even as first-line salvage, when teratoma or somatic malignancy is suspected.
Ozawa Y, Yamamoto K, Sugawara S
… +6 more, Niho S, Okamoto H, Hotta K, Okamoto I, Ikeda N, Yamamoto N
Br J Cancer
· 2026 Jun · PMID 41957135
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BACKGROUND: Concurrent chemoradiotherapy (cCRT) is a pivotal component in locally advanced non-small cell lung cancer (NSCLC) treatment; however, exploration of factors that impact its efficacy has been limited. METHODS:...BACKGROUND: Concurrent chemoradiotherapy (cCRT) is a pivotal component in locally advanced non-small cell lung cancer (NSCLC) treatment; however, exploration of factors that impact its efficacy has been limited. METHODS: We analyzed individual data of 1165 patients with locally advanced NSCLC enrolled in randomized phase II/III trials of cCRT between 1999 and 2016. Least absolute shrinkage and selection operator (LASSO) regression was applied to identify factors associated with 3-year progression-free survival (PFS). Cox regression was applied to adjust for key clinical variables. RESULTS: The 3- and 5-year PFS rates were 19.7% and 14.3%, respectively (median PFS: 9.7 months). The 3- and 5-year overall survival rates were 56.7% and 42.9%, respectively (median OS: 25.7 months). LASSO regression identified age, lower lobe tumor location, weight loss (≥5% within 6 months), smoking index, and histology as predictors of PFS. Lower lobe tumors and weight loss independently predicted shorter PFS (lower lobe: hazard ratio 1.29; 95% CI, 1.02-1.64; P = 0.036). Lower lobe tumors also had more pneumonitis (55.8% vs. 43.4%; grade ≥3: 11.0% vs. 4.3%) and in-field recurrence (60.2% vs. 51.4%). CONCLUSION: Primary tumor location should be carefully considered in clinical practice and during the development of treatment strategies for locally advanced NSCLC.