Mukai S, Sato T, Kamei Y
… +6 more, Kato K, Mishiro-Sato E, Kondo-Ida L, Yabuta N, Hiroshima K, Sekido Y
Br J Cancer
· 2026 May · PMID 41792509
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BACKGROUND: Mesothelioma is an aggressive malignancy with limited therapeutic options. Genetic alterations involving the Hippo pathway are commonly observed. O-GlcNAcylation is frequently elevated in cancer and drives tu...BACKGROUND: Mesothelioma is an aggressive malignancy with limited therapeutic options. Genetic alterations involving the Hippo pathway are commonly observed. O-GlcNAcylation is frequently elevated in cancer and drives tumour progression. However, its relationship with Hippo pathway dysfunction in mesothelioma remains unclear. METHODS: O-GlcNAcylation levels were examined in mesothelioma samples and cell lines, and O-GlcNAcylated proteins were detected by mass spectrometry. The functional impact of O-GlcNAcylation was determined by quantifying nuclear transport dynamics using light-induced live-cell imaging. Genetic and pharmacological inhibition of O-GlcNAcylation was evaluated in vitro. Treatment with the nuclear export inhibitor KPT-330 (Selinexor) was assessed in vitro and in a mouse xenograft model. RESULTS: O-GlcNAcylation was markedly increased in mesothelioma cells with Hippo pathway inactivation. This modification primarily targeted nuclear pore complex proteins, including NUP214 and NUP62, and significantly accelerated nuclear export rates. Suppression of O-GlcNAcylation diminished nuclear export and inhibited cell proliferation. Importantly, pharmacological blockade of nuclear export using KPT-330 suppressed cell growth in vitro and produced significant antitumour effects in vivo. CONCLUSIONS: These findings demonstrate O-GlcNAcylation-driven enhancement of nuclear export as a therapeutically actionable vulnerability in mesothelioma with inactivation of the Hippo pathway.
Li M, Li Y, Li C
… +10 more, Liu A, Liu Y, Li Y, Xiao J, Zhang D, Jin Y, Wang G, Pang X, Jiang K, Yin Y
Br J Cancer
· 2026 May · PMID 41792508
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BACKGROUND: Colorectal cancer (CRC) exhibits distinct bacterial community compositions compared to healthy mucosae, which intimately correlate with CRC clinical outcomes. There is a lack of explanation for the inducement...BACKGROUND: Colorectal cancer (CRC) exhibits distinct bacterial community compositions compared to healthy mucosae, which intimately correlate with CRC clinical outcomes. There is a lack of explanation for the inducements of microbiota remodelling. METHODS: FISH experiments and 16S rRNA sequencing were conducted to determine the inducements of various bacterial colonisation within tissues. Community cultivation was conducted to estimate the capacity of tumours to remodel bacterial communities. Metagenomic analyses were utilised to determine the remodelled communities of CRC with distant metastasis. Scratch tests and three-dimensional (3D) cultivation were employed to investigate the influence of specific taxa on tumour cell behaviours. RESULTS: Colorectal tumours exhibit heterogeneous and individualised preferences in constantly remodelling intratumoural bacterial florae. Various degrees of colorectal gland differentiation within tumours cause heterogeneous intratumoural bacterial colonisation. CRC progression further alters bacterial community composition. Particularly, Prevotella is significantly enriched in the newly established communities colonising the primary foci of metastatic CRC. Furthermore, Prevotella intermedia (P. intermedia) promotes the invasion, migration, and ectopic tumorigenesis of CRC cells. CONCLUSIONS: Individual evaluation of the preference of tumours in microbiota may pave the way to the development of CRC therapeutic strategies, and Prevotella is an emerging genus worthy of clinical attention.
Nishihara K, Yamaji T, Lu Y
… +7 more, Nakano S, Kuchiba A, Inoue M, Tsugane S, Sawada N, Iwasaki M, Japan Public Health Center-based Prospective Study Group
Br J Cancer
· 2026 May · PMID 41787051
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BACKGROUND: This study aimed to elucidate the impact of systemic shifts towards increased oxidative or antioxidative potential on cancer development and suppression. Given that longitudinal studies on cancer associations...BACKGROUND: This study aimed to elucidate the impact of systemic shifts towards increased oxidative or antioxidative potential on cancer development and suppression. Given that longitudinal studies on cancer associations are limited for plasma levels of derivatives of reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP), we investigated the associations of these robust biomarkers with risk of overall and multiple site-specific cancers. METHODS: We designed a case-cohort study within a large Japanese population-based prospective study. Plasma d-ROM and BAP were measured in 4718 cancer cases and 4815 randomly selected subcohort individuals, who were followed for a mean period of 15.5 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a weighted Cox proportional hazards model. RESULTS: Compared to the lowest quartiles, the highest quartiles of d-ROM showed a multivariable adjusted HR of 1.69 (95% CI = 1.08-2.64; p = 0.02) for hepatocellular carcinoma and 1.32 (95% CI = 1.01-1.72; p = 0.01) for lung cancer. Conversely, the highest quartile of BAP for gastric cancer was 0.80 (95% CIs = 0.63-1.01; p = 0.03). CONCLUSIONS: These findings suggest a potential impact of oxidation and antioxidation on cancer development at specific sites.
Hunter JD, Hetherington K, McGillycuddy M
… +12 more, Wakefield CE, Tucker KM, O'Brien TA, McGill BC, Fuentes-Bolanos NA, Bhatia K, Padhye B, Grant A, Barlow-Stewart K, Warby M, Courtney EK, Peate M
Br J Cancer
· 2026 May · PMID 41787050
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BACKGROUND: Germline genomic sequencing (GGS) is increasingly offered to children with cancer. We explored families' experiences of consent, result-disclosure, and satisfaction in the PREDICT study, a standalone trio-GGS...BACKGROUND: Germline genomic sequencing (GGS) is increasingly offered to children with cancer. We explored families' experiences of consent, result-disclosure, and satisfaction in the PREDICT study, a standalone trio-GGS study of unselected, newly-diagnosed patients ( ≤ 21 yrs). METHODS: Using a convergent parallel mixed-methods design, parents and children ( ≥ 12 yrs) completed questionnaires at baseline/post-consent (T0), results-return (T1), and for parents, one-year post-enrolment (T2). Parents completed T1 interviews. RESULTS: 187/248 parents (mean:40.4 yrs) and 19/32 children (mean:14.9 yrs) from 128/144 families participated; 49 parents were interviewed. Few reported thoroughly reading consent materials and consent-related distress was low, though higher among parents with lower-income (p = 0.001) or below-average genetics knowledge (p = 0.027). At result-return, participants reported moderate distress, with no differences by result type (p = 0.118). Satisfaction was high (median: parents 98/100, children 87/100), 96% of parents and 60% of children would recommend PREDICT, and parents reported minimal regret (mean:15.74/100). Qualitative data revealed that cancer diagnosis-related distress influenced consent comprehension and potentially impeded parents' ability to consider study implications for themselves. Emotional reactions to results ranged from relief to distress, regardless of findings. Communication and trust shaped experiences. CONCLUSIONS: Consent for trio-GGS at cancer diagnosis is complex, requiring flexible, tailored processes. Clear, timely communication from trusted clinicians is key to improving family experiences.
Turnham DJ, French R, Frame FM
… +3 more, Meniel VS, Maitland NJ, Clarkson RWE
Br J Cancer
· 2026 May · PMID 41776063
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BACKGROUND: Prostate cancer is a leading cause of cancer-associated death in men worldwide. Inhibition of the Cellular FLICE-like Inhibitory Protein (cFLIP), which is overexpressed in prostate cancer, alongside TRAIL tre...BACKGROUND: Prostate cancer is a leading cause of cancer-associated death in men worldwide. Inhibition of the Cellular FLICE-like Inhibitory Protein (cFLIP), which is overexpressed in prostate cancer, alongside TRAIL treatment can trigger apoptosis and suppress cancer stem cell (CSC) activity in different cancer types but has not been fully explored in prostate cancer. METHODS: Established and primary prostate cancer lines were treated with the cFLIP inhibitor, OH14, in combination with recombinant TRAIL to investigate changes in viability and colony forming potential. Patient-derived xenograft (PDX) tumour cells were treated ex vivo and re-transplanted into mice in limiting dilution assays. Docetaxel resistant PC-3 cells were also treated with OH14 +/- docetaxel, while PDX tumours were treated in vivo with this combination. RESULTS: Combined OH14 and TRAIL treatment induced a potent apoptotic response in prostate cancer cells, significantly reducing viability and CSC activity compared to single agents. OH14 also sensitised tumour cells to docetaxel both in vitro and in vivo. CONCLUSIONS: Inhibition of cFLIP in combination with either TRAIL or docetaxel has the potential to be used as a novel therapeutic approach to provide more potent, long-lasting benefits to men with prostate cancer.
Ball M, Beck S, Wlochowitz D
… +23 more, Fuchs T, Lorenz K, Zgorzelski C, Pallares Robles A, Allgäuer M, Volckmar AL, Goldschmid H, Ourailidis I, Brandt R, Christopoulos P, Thomas M, Seker-Cin H, Fink A, Schnecko F, Neumann O, Menzel M, Kirchner M, Fioretos T, Schirmacher P, Peters S, Budczies J, Stenzinger A, Kazdal D
Br J Cancer
· 2026 Apr · PMID 41772276
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Jiang P, Zhou X, Cai Y
… +13 more, Yang J, Zhou K, Tong Y, Huang C, Dong B, Qiu H, Xu X, Niu J, Shen C, Xia X, Zhang Y, Song X, Wan L
Br J Cancer
· 2026 May · PMID 41772275
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BACKGROUND: Immune reconstitution is critical for outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its prognostic role in haploidentical peripheral blood stem cell transplantation (haplo...BACKGROUND: Immune reconstitution is critical for outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its prognostic role in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) remains unclear. METHODS: We retrospectively analysed 577 patients who underwent T-cell replete haplo-PBSCT between 2016 and 2024. Longitudinal reconstitution of CD4⁺, CD8⁺ T cells and their subsets, CD3⁺CD69⁺, CD3⁺HLA-DR⁺ T cells, NK cells and B cells was assessed from 1 to 12 months post-transplant. Cox regression and causal mediation analyses were performed to identify prognostic associations and mechanisms. RESULTS: Early and robust regulatory T cell (Treg) reconstitution significantly reduced transplant-related mortality (TRM) and improved overall survival. Naïve CD8⁺ T cell recovery correlated with reduced TRM and relapse. Higher late CD3⁺CD69⁺ T cells were linked to decreased relapse risk. Sustained B cell reconstitution reduced TRM and was associated with a lower incidence of moderate-to-severe chronic graft-versus-host disease. Early Treg reconstitution was associated with lower cytomegalovirus (CMV) reactivation. Mediation analysis revealed that Treg recovery reduced TRM partially through suppression of CMV reactivation (ACME = -0.22, p = 0.032). CONCLUSION: Distinct lymphocyte subset reconstitution profiles predict transplant outcomes in haplo-PBSCT. Early Treg recovery, partly by limiting CMV reactivation, may serve as a target for immune-guided intervention.
Harris M, French DP, Clare K
… +5 more, Harvie M, Wilson DT, Brown J, Jayne D, Renehan AG
Br J Cancer
· 2026 Apr · PMID 41772274
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Obesity is associated with increased risk of at least 13 cancer types. Evidence from bariatric surgery cohorts and some behavioural intervention trials supports the notion that weight loss can prevent obesity-related can...Obesity is associated with increased risk of at least 13 cancer types. Evidence from bariatric surgery cohorts and some behavioural intervention trials supports the notion that weight loss can prevent obesity-related cancers. The introduction of glucagon-like peptide (GLP)-1 agonist drugs has rapidly revolutionised pharmacotherapy options. A cancer prevention clinical trial would be complex, lengthy, and costly; therefore, we undertook an international expert consensus to assess the need for and design of a weight-loss intervention cancer prevention trial. We used a combination of two nominal group meetings, sandwiching 3 Delphi rounds. A panel of 54 international, multi-disciplinary researchers was established, informed by patient groups. Feedback was incorporated iteratively, and borderline statements, those that did not reach consensus, were addressed in a final meeting. Through the Delphi rounds, retention rates were high (98%, 85%, 88%). Consensus was achieved on 25 statements. Including: (i) there is a need for clinical trial evidence to inform obesity-related cancer prevention strategies; (ii) a trial should reflect high-risk populations; (iii) trials should prioritise GLP-1 agonists; and (iv) future research should explore mechanistic pathways and relevant cancer precursors. This consensus underscores the need for trial evidence to inform strategies for obesity-related cancer prevention.
Metser U, Dayes IS, Parpia S
… +8 more, Eisen AF, Hodgson N, Cil TD, George R, Blanchette P, Arnaout A, Chan A, Levine MN
Br J Cancer
· 2026 May · PMID 41772273
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PURPOSE: Patients with locally advanced breast cancer (LABC) undergo staging tests. In the absence of metastases, they may receive combined modality therapy with curative intent. A randomised controlled trial (RCT) in pa...PURPOSE: Patients with locally advanced breast cancer (LABC) undergo staging tests. In the absence of metastases, they may receive combined modality therapy with curative intent. A randomised controlled trial (RCT) in patients with locally advanced breast cancer (LABC) compared staging using 18F-FDG PET-CT versus the usual CT chest/abdomen and bone scan, with the primary outcome being upstaging to Stage 4. Because of concern regarding the lower FDG-avidity of invasive lobular breast cancer (ILBC) compared to invasive ductal cancer (IDC), patients with ILBC were not eligible for the RCT. METHODS: A prospective cohort study in patients with ILBC and TNM stage III or IIb (T3N0) was conducted contemporaneously to the RCT. Consenting patients from six regional cancer centres in Ontario all underwent whole body 18F-FDG PET-CT, CT with contrast of the chest/abdomen, and a bone scan. The primary endpoint was upstaging to stage IV. (ClinicalTrials.gov identifier: NCT02751710). RESULTS: Between December 2016 and April 2022, 41 patients with ILBC were enroled: 38 undergoing all three imaging tests. Five patients (13.2%) were upstaged due to distant disease; all had positive PET-CT scans. Among these five patients, two were positive on both CT and bone scan, two on either CT or bone scan, and one on neither. Six of 38 (15.8%) primary ILBC tumours lacked FDG uptake and the mean standard uptake value was 4.4 (3.2). CONCLUSION: In this cohort, 18F-FDG PET-CT detected all cases of metastatic spread.
Dunneram Y, Lee JY, Watling CZ
… +28 more, Lawson I, Parsaeian M, Fraser GE, Butler FM, Prabhakaran D, Shridhar K, Kondal D, Mohan V, Ali MK, Narayan KMV, Tandon N, Tong TYN, Travis RC, Chiu THT, Lin MN, Lin CL, Yang HC, Liang YJ, Greenwood DC, Reeves GK, Papier K, Floud S, Sinha R, Liao LM, Loftfield E, Cade JE, Key TJ, Perez-Cornago A
Br J Cancer
· 2026 Apr · PMID 41748939
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BACKGROUND: Vegetarian diets might influence cancer risk. METHODS: We studied 1,645,555 meat eaters, 57,016 poultry eaters, 42,910 pescatarians, 63,147 vegetarians and 8849 vegans in 9 cohorts (UK, US, Taiwan, India). Af...BACKGROUND: Vegetarian diets might influence cancer risk. METHODS: We studied 1,645,555 meat eaters, 57,016 poultry eaters, 42,910 pescatarians, 63,147 vegetarians and 8849 vegans in 9 cohorts (UK, US, Taiwan, India). After a median 16 years follow-up, incident cancers were: 4504 mouth and pharynx, 1308 oesophagus (squamous cell), 2105 oesophagus (adenocarcinoma), 3578 stomach, 30,528 colorectum, 2970 liver, 8030 pancreas, 3077 lung (never smokers), 61,368 breast, 11,220 endometrium, 8076 ovary, 45,946 prostate, 7193 kidney, 6869 bladder, 11,651 non-Hodgkin lymphoma, 4658 multiple myeloma and 7306 leukaemia. Multivariable Cox regression was used to estimate cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs), and the results were combined using meta-analysis. RESULTS: Compared to meat eaters, poultry eaters had lower risk of prostate cancer (0.93, 0.88-0.98), pescatarians had lower risks of colorectal (0.85, 0.77-0.93), breast (0.93, 0.88-0.98) and kidney cancer (0.73, 0.58-0.93), vegetarians had lower risks of cancers of the pancreas (0.79, 0.65-0.97), breast (0.91, 0.86-0.97), prostate (0.88, 0.79-0.97), kidney (0.72, 0.57-0.92) and multiple myeloma (0.69, 0.51-0.93) but higher risk of squamous cell carcinoma of the oesophagus (1.93, 1.30-2.87), and vegans had higher risk of colorectal cancer (1.40, 1.12-1.75). CONCLUSIONS: Vegetarian diets might influence risk for several cancers. The generalisability should be considered cautiously.
Hale J, Gilbert T, Stott M
… +10 more, Whelan P, Jackson R, Wong H, McKay M, Ghaneh P, Halloran C, Faluyi O, Dunne D, Neoptolemos JP, Palmer D
Br J Cancer
· 2026 Apr · PMID 41741817
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BACKGROUND: Pancreatic cancer remains a significant challenge to diagnose and treat, with considerable regional variation in management and outcomes. This study aimed to evaluate real-world outcomes of patients receiving...BACKGROUND: Pancreatic cancer remains a significant challenge to diagnose and treat, with considerable regional variation in management and outcomes. This study aimed to evaluate real-world outcomes of patients receiving adjuvant treatment for pancreatic cancer at a single centre in Northwest England over an 11-year period. METHODS: Data were collected retrospectively on all patients who underwent surgery for pancreatic ductal adenocarcinoma between 2009 and 2020. Collected data included patient demographics, surgical details and adjuvant treatment received, including number of chemotherapy cycles and dose reductions. RESULTS: 30-day/inpatient mortality was low (2.4%). Adjuvant chemotherapy delivery rates were high (82%) with 67.4% of patients completing the intended number of cycles. There was no additional survival benefit for patients who started chemotherapy within 8 weeks post-surgery compared to those who began later. Dose reductions did not impact survival, provided patients completed the full course of treatment (mOS 27.5 months vs. 28.5 months; HR 1.14, 95% CI 0.76-1.70 p = 0.513). Following centralisation of care, a greater proportion of patients commenced adjuvant treatment (86% vs 69% p < 0.05). CONCLUSION: A high proportion of patients received adjuvant treatment, with a centralised clinic model leading to increased rates of adjuvant chemotherapy delivery. Completion of the full chemotherapy course was more critical than dose intensity. Larger prospective studies are needed to investigate the factors contributing to regional variations.
Schlicke P, Korangath P, Pan X
… +7 more, Ercan C, Gabrielson K, Werhane L, Yuan Y, Benzekry S, Ivkov R, Enderling H
Br J Cancer
· 2026 Apr · PMID 41735583
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BACKGROUND: Cancer is a systemic disease with most deaths attributed to metastatic burden. Primary and metastatic tumors, albeit at different anatomic locations, are interconnected through multiple biological processes....BACKGROUND: Cancer is a systemic disease with most deaths attributed to metastatic burden. Primary and metastatic tumors, albeit at different anatomic locations, are interconnected through multiple biological processes. Pre-clinical and clinical observations of growth acceleration of metastases after surgery, or abscopal effects outside the radiation field are widely reported, yet reliably triggering favorable and avoiding unfavorable systemic responses remains an unmet clinical need. Understanding local and systemic tumor interaction dynamics will help guide future treatments. METHODS: We analyze the data of multiple in vivo tumor models. We formalize the systemic interplay of tumors as mathematical differential equation and calibrate parameters for each cell line and mouse type. Using model selection metrics, we identify classic tumor growth models with a novel shared carrying capacity parsimoniously describe the pan-cancer experimental data. RESULTS: Shared systemic carrying capacity, metastatic spread potential, and metastatic growth rates differ across tested cell lines and mouse strains. Bi-directional concomitant systemic interconnectivity explains the observed metastatic explosion after primary tumor surgery. DISCUSSION: Future investigations should reproduce this analysis in clinical settings and evaluate whether this shared carrying capacity model could help stratify patients at risk of metastatic disease below clinical detectability and inform strategies to control oligometastatic cancer.
Br J Cancer
· 2026 May · PMID 41735582
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Evidence from conventional and Mendelian Randomisation epidemiological studies support the conclusion that obesity is causally associated with increased risk of several common cancer types. Some evidence, notably from qu...Evidence from conventional and Mendelian Randomisation epidemiological studies support the conclusion that obesity is causally associated with increased risk of several common cancer types. Some evidence, notably from quasi-experimental bariatric surgery studies, support the concept that sustained long-term weight loss in individuals is associated with reduction of cancer incidence, particularly in women. Yet, there are no authoritative public health policies directed specifically at large-scale weight management interventions to prevent obesity-related cancers. At least two adversities conspire against public health success: (i) awareness of the causal link between obesity and cancer risk; and (ii) lifestyle interventions are associated with only moderate weight loss that is generally not sustained long enough to result in clinically meaningful cancer prevention. However, there is now a revolution of effective pharmacotherapy for obesity, namely glucagon-like-peptide (GLP)-1 agonists and their extended family of dual and triple agonists, which leads to substantial rates of weight loss, sustained while individuals continue to take the drug. There is now a key new cancer prevention research question, whether this drug class might significantly reduce cancer risk with long-term use. The logistics of addressing this question in a clinical trial setting are discussed and potential strategies to overcome these challenges are proposed.
Kye YH, Moon SJ, Cha HR
… +4 more, Kim TH, Eom JY, Myung JK, Kong G
Br J Cancer
· 2026 Apr · PMID 41735581
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BACKGROUND: Tamoxifen resistance remains a significant obstacle in oestrogen receptor (ER)-positive breast cancer. The function of absent, small, or homeotic 2-like protein (ASH2L) at chr8p11.23 in breast cancer is not e...BACKGROUND: Tamoxifen resistance remains a significant obstacle in oestrogen receptor (ER)-positive breast cancer. The function of absent, small, or homeotic 2-like protein (ASH2L) at chr8p11.23 in breast cancer is not entirely understood. METHODS: Survival analysis according to ASH2L expression was examined using METABRIC (n = 968) and KM plotter (n = 150). ASH2L-mediated tamoxifen resistance and CSC activity were evaluated through in vitro assays, including SRB, colony formation, tumour sphere formation, and FACS, and in vivo xenograft models. RNA-seq and ChIP-qPCR were performed to elucidate the underlying mechanism. RESULTS: High ASH2L amplification correlated with poor prognosis in tamoxifen-treated ER-positive breast cancer patients. ASH2L induces tamoxifen resistance and promotes CSC activity through ITGA6/ERK signalling in an H3K4me3-dependent manner. Mechanistically, ASH2L is recruited to HIF2A and ITGA6 promoters, enhancing H3K4me3 and H3K27ac and reducing HDAC1 and H3K27me3, thereby activating ERK signalling. Genetic or pharmacological inhibition of ASH2L, ITGA6, or ERK abolished ASH2L-induced CSC activity. Although ERK inhibition alone did not rescue tamoxifen resistance, its combination with tamoxifen overcame resistance in vitro and in vivo. CONCLUSIONS: ASH2L promotes tamoxifen resistance and CSC activity through ITGA6/ERK signalling. Combination therapy with tamoxifen and an ERK inhibitor may be a promising strategy for ER-positive breast cancer patients with ASH2L overexpression.
Fennell L, Liu C, Kane A
… +8 more, Tria S, Borowsky J, Chai L, Randall-Demllo S, McKeone D, Bond C, Leggett B, Whitehall V
Br J Cancer
· 2026 Apr · PMID 41731118
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BACKGROUND: Serrated neoplasia arises from serrated precursor lesions. Hyperplastic polyps commonly activate MAPK signalling, initiated by BRAF or KRAS mutation, but premalignant KRAS-mutant sessile serrated lesions are...BACKGROUND: Serrated neoplasia arises from serrated precursor lesions. Hyperplastic polyps commonly activate MAPK signalling, initiated by BRAF or KRAS mutation, but premalignant KRAS-mutant sessile serrated lesions are rare. Here, we model Kras- and Braf-mutant neoplasia in vivo comparing histological, transcriptomic, and epigenetic changes. METHODS: Temporospatial activation of oncogenic Braf or Kras was induced in murine intestine. Differential expression, methylation and pathways analyses identified oncogene-specific alterations. RESULTS: Prolonged exposure to oncogenic Braf is associated with a time-dependent accumulation of murine serrated precursors (mSP, P = 3 × 10), and murine serrated lesions (mSL) and invasive cancer (8 × 10). Kras-mutants acquired fewer mSPs (P = 0.06) and lower probability of developing mSLs (P = 0.004). Kras-mutant mSLs rarely develop aberrant WNT signalling (1/23). Transcriptomic profiles diverged, with Braf-mutant intestines showing enriched immune and inflammatory signalling. Deconvolution analysis revealed Braf-mutants had comparably higher macrophage infiltrate (P = 0.025) and upregulation of M1 macrophage gene sets (P = 0.0008). Both mutations showed accumulating DNA methylation, however, an attenuated rate in a subset of CpG sites (1306) was observed in Kras-mutant intestine. CONCLUSION: Kras mutation can induce serrated neoplasia, but with significantly greater latency period and lower penetrance compared to Braf. Kras-mutant neoplasms display an attenuated CIMP-like phenotype, rarely developing aberrant WNT signalling. These data refine our understanding of MAPK-induced intestinal neoplasia.
Ree AH, Bousquet PA, Visnovska T
… +13 more, Lüders T, Geisler BP, Wang S, Bordin DL, Nilsen HL, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Berg JP, Flatmark K, Meltzer S
Br J Cancer
· 2026 Apr · PMID 41731117
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BACKGROUND: The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc...BACKGROUND: The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients' systemic inflammation might provide insights into responsiveness to the METIMMOX regimen. METHODS: Patients received either oxaliplatin-based chemotherapy (control group) or alternating two cycles each of chemotherapy and nivolumab (experimental group), with progression-free survival (PFS) as the primary endpoint. Tumour biopsies were sequenced with the TruSight Oncology 500 assay. RESULTS: The median tumour mutational burden (TMB; in mutations/megabase) was 8 (range, 1-13). The experimental-arm patients with TMB ≥9 or BRAF-V600E mutation (n = 17) achieved median PFS of 19.8 months (95% confidence interval, 11.3-28.3), longer (p = 0.0090) than experimental-arm patients with TMB < 9 not BRAF-V600E (n = 19) and control-arm patients with either TMB and BRAF status combination (n = 31). With TMB ≥9 or BRAF-V600E and normal, non-inflammatory level of C-reactive protein when starting nivolumab (n = 11), median PFS was 35.0 months (95% confidence interval, 6.8-63.0; p < 0.0001). CONCLUSIONS: TMB, somatic BRAF status and systemic inflammation should be prospectively investigated as practical biomarkers for predicting potential responsiveness to immune checkpoint inhibitors in metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer.
Woodford R, Lorigan P, Oudit D
… +3 more, Abdulgawad A, Thistlethwaite F, Lim KHJ
Br J Cancer
· 2026 Jun · PMID 41708938
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Tumour infiltrating lymphocyte (TIL) therapy offers the potential for durable clinical benefit in select patients with advanced melanoma, especially after progression on treatment with immune checkpoint inhibitors and/or...Tumour infiltrating lymphocyte (TIL) therapy offers the potential for durable clinical benefit in select patients with advanced melanoma, especially after progression on treatment with immune checkpoint inhibitors and/or targeted therapies. The 2024 FDA approval of Lifileucel (Amtagvi), a commercially manufactured autologous TIL product, marks a key milestone in integrating advanced therapy medicinal products (ATMPs) into routine care for solid tumours. Health Canada has since approved Lifileucel, with regulatory and funding decisions across the UK and Europe still pending. In this Perspective, we review the evidence base and outline key considerations for national adoption of TIL therapy. Despite promising results from clinical trials, TIL therapy requires complex coordination, including patient selection, tumour procurement, manufacturing logistics, lymphodepletion, and IL-2 administration; all contingent on specialised infrastructure and well-considered integrated care pathways. While commercial centralisation may ease logistical barriers, the high cost of TIL therapy necessitates careful health economic evaluation. A nationally coordinated effort is required to harmonise clinical prioritisation strategies, maintain oversight by multidisciplinary specialist tumour boards, and consider investment in future-proof decentralised manufacturing capacity. Collaborations and peer support such as through the Advanced Therapy Treatment Centre (ATTC) Network will facilitate phased, experience-led rollout with equity-focused service design.