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A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis.
No full textSolid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment
The ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): Results from the OSIPI-Dynamic Contrast-Enhanced challenge.
No full textPURPOSE: K trans has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for K trans quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging-Dynamic Contrast-Enhanced (OSIPI-DCE) challenge was designed to benchmark methods to better help the efforts to standardize K trans measurement. METHODS: A framework was created to evaluate K trans values produced by DCE-MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for K trans quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' K trans values, the applied software, and a standard operating procedure. These were evaluated using the proposed OSIP I gold score defined with accuracy, repeatability, and reproducibility components. RESULTS: Across the 10 received submissions, the OSIP I gold score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0-1 = lowest-highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in K trans analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility. CONCLUSIONS: This study reports results from the OSIPI-DCE challenge and highlights the high inter-software variability within K trans estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real-world clinical setting, many of these tools may perform differently with different benchmarking methodology
Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade.
No full textMutant selective drugs targeting the inactive, GDP-bound form of KRASG12C have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RASG12C in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive. In an immune inflamed model, RAS and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory. In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade
NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance.
No full textThe Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically1,2. This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells3. However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the 'writer' of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy
T-cell receptor determinants of response to chemoradiation in locally-advanced HPV16-driven malignancies.
No full textBACKGROUND: The effect of chemoradiation on the anti-cancer immune response is being increasingly acknowledged; however, its clinical implications in treatment responses are yet to be fully understood. Human papillomavirus (HPV)-driven malignancies express viral oncogenic proteins which may serve as tumor-specific antigens and represent ideal candidates for monitoring the peripheral T-cell receptor (TCR) changes secondary to chemoradiotherapy (CRT). METHODS: We performed intra-tumoral and pre- and post-treatment peripheral TCR sequencing in a cohort of patients with locally-advanced HPV16-positive cancers treated with CRT. An in silico computational pipeline was used to cluster TCR repertoire based on epitope-specificity and to predict affinity between these clusters and HPV16-derived epitopes. RESULTS: Intra-tumoral repertoire diversity, intra-tumoral and post-treatment peripheral CDR3β similarity clustering were predictive of response. In responders, CRT triggered an increase peripheral TCR clonality and clonal relatedness. Post-treatment expansion of baseline peripheral dominant TCRs was associated with response. Responders showed more baseline clustered structures of TCRs maintained post-treatment and displayed significantly more maintained clustered structures. When applying clustering by TCR-specificity methods, responders displayed a higher proportion of intra-tumoral TCRs predicted to recognise HPV16 peptides. CONCLUSIONS: Baseline TCR characteristics and changes in the peripheral T-cell clones triggered by CRT are associated with treatment outcome. Maintenance and boosting of pre-existing clonotypes are key elements of an effective anti-cancer immune response driven by CRT, supporting a paradigm in which the immune system plays a central role in the success of CRT in current standard-of-care protocols
Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.
No full textUNLABELLED: Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis. SIGNIFICANCE: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897
European Society of Radiotherapy and Oncology (ESTRO) strategy 2024-2026: Growth and diversification in a rapidly changing world.
No full textIn 2019, the European Society of Radiotherapy and Oncology (ESTRO) published its 2030 Vision "Radiation Oncology, Optimal Health, For All, Together". However, in 2020, the global pandemic, coinciding with the Society's 40th anniversary, had long-term consequences on global behaviours and on the financial environment for scientific associations worldwide. In 2022, ESTRO conducted a survey among its members, revealing their strong appreciation for networking opportunities and the creation of high-quality interdisciplinary scientific content. In response to the survey findings and to address the evolving landscape following the COVID pandemic, ESTRO initiated a strategic review process to respond to, and refocus on, the opportunities and challenges ahead. This paper, marking a turning point in ESTRO's strategy for achieving its Vision 2030 in a post-pandemic era, describes the 2022-23 strategic review process, discussions, and consequent recommendations. The comprehensive strategic review process involved: (i) pre-meeting preparations with surveys and strategic documents; (ii) a carefully themed three-day retreat in Brussels incorporating a blend of plenary sessions, workshops focusing on ESTRO's role, value creation and capture, strategic objectives; and (iii) a post-retreat phase including qualitative analysis and development of action plans. The strategic review emphasized the need for adaptive tactics for scientific associations to remain current and productive in the face of changing global conditions. The development of key strategic goals for the years 2024-2026 focused on improving research impact, strengthening and diversifying ESTRO's educational offerings and fostering proactive and mutually beneficial partnerships. The Board approved these objectives, alongside prioritising digital innovation, financial sustainability, and community engagement for ESTRO's continued growth and development. In essence, ESTRO aims to advocate, empower, expand, and diversify its community, with the overarching goal of enhancing cancer care for patients in Europe, and beyond
A pan-cancer analysis of the frequency of DNA alterations across cell cycle activity levels.
No full textPan-cancer genomic analyses based on the magnitude of pathway activity are currently lacking. Focusing on the cell cycle, we examined the DNA mutations and chromosome arm-level aneuploidy within tumours with low, intermediate and high cell-cycle activity in 9515 pan-cancer patients with 32 different tumour types. Boxplots showed that cell-cycle activity varied broadly across and within all cancers. TP53 and PIK3CA mutations were common in all cell cycle score (CCS) tertiles but with increasing frequency as cell-cycle activity levels increased (P < 0.001). Mutations in BRAF and gains in 16p were less frequent in CCS High tumours (P < 0.001). In Kaplan-Meier analysis, patients whose tumours were CCS Low had a longer Progression Free Interval (PFI) relative to Intermediate or High (P < 0.001) and this significance remained in multivariable analysis (CCS Intermediate: HR = 1.37; 95% CI 1.17-1.60, CCS High: 1.54; 1.29-1.84, CCS Low = Ref). These results demonstrate that whilst similar DNA alterations can be found at all cell-cycle activity levels, some notable exceptions exist. Moreover, independent prognostic information can be derived on a pan-cancer level from a simple measure of cell-cycle activity
Genetic landscape of interval and screen detected breast cancer.
No full textInterval breast cancers (IBCs) are cancers diagnosed between screening episodes. Understanding the biological differences between IBCs and screen-detected breast-cancers (SDBCs) has the potential to improve mammographic screening and patient management. We analysed and compared the genomic landscape of 288 IBCs and 473 SDBCs by whole genome sequencing of paired tumour-normal patient samples collected as part of the UK 100,000 Genomes Project. Compared to SDBCs, IBCs were more likely to be lobular, higher grade, and triple negative. A more aggressive clinical phenotype was reflected in IBCs displaying features of genomic instability including a higher mutation rate and number of chromosomal structural abnormalities, defective homologous recombination and TP53 mutations. We did not however, find evidence to indicate that IBCs are associated with a significantly different immune response. While IBCs do not represent a unique molecular class of invasive breast cancer they exhibit a more aggressive phenotype, which is likely to be a consequence of the timing of tumour initiation. This information is relevant both with respect to treatment as well as informing the screening interval for mammography
Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study.
No full textBACKGROUND: This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. METHODS: Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. FINDINGS: During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01-1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03-1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10 μg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12-1.79; P = 0.004; I2 = 90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. INTERPRETATION: Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. FUNDING: Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198)