ICR Publications RepositoryThe ICR (DSpace) digital repository system captures, stores, indexes,
preserves, and distributes digital research material.
https://repository.icr.ac.uk:4432024-03-19T01:44:31Z2024-03-19T01:44:31ZMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting.Pomella, SCassandri, MD'Archivio, LPorrazzo, ACossetti, CPhelps, DPerrone, CPezzella, MCardinale, AWachtel, MAloisi, SMilewski, DColletti, MSreenivas, PWalters, ZSBarillari, GDi Giannatale, AMilano, GMDe Stefanis, CAlaggio, RRodriguez-Rodriguez, SCarlesso, NVakoc, CRVelardi, ESchafer, BWGuccione, EGatz, SAWasti, AYohe, MIgnatius, MQuintarelli, CShipley, JMiele, LKhan, JHoughton, PJMarampon, FGryder, BEDe Angelis, BLocatelli, FRota, Rhttps://repository.icr.ac.uk/handle/internal/61892024-03-15T09:16:18Z2023-12-15T00:00:00ZMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting.
Pomella, S; Cassandri, M; D'Archivio, L; Porrazzo, A; Cossetti, C; Phelps, D; Perrone, C; Pezzella, M; Cardinale, A; Wachtel, M; Aloisi, S; Milewski, D; Colletti, M; Sreenivas, P; Walters, ZS; Barillari, G; Di Giannatale, A; Milano, GM; De Stefanis, C; Alaggio, R; Rodriguez-Rodriguez, S; Carlesso, N; Vakoc, CR; Velardi, E; Schafer, BW; Guccione, E; Gatz, SA; Wasti, A; Yohe, M; Ignatius, M; Quintarelli, C; Shipley, J; Miele, L; Khan, J; Houghton, PJ; Marampon, F; Gryder, BE; De Angelis, B; Locatelli, F; Rota, R
Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.
2023-12-15T00:00:00ZMultiparametric bone MRI targeting aides lesion selection for CT-guided sclerotic bone biopsies in metastatic castrate resistant prostate cancer.Donners, RFigueiredo, IWestaby, DKoh, D-MTunariu, NCarreira, Sde Bono, JSFotiadis, Nhttps://repository.icr.ac.uk/handle/internal/61882024-03-15T09:16:13Z2023-12-15T00:00:00ZMultiparametric bone MRI targeting aides lesion selection for CT-guided sclerotic bone biopsies in metastatic castrate resistant prostate cancer.
Donners, R; Figueiredo, I; Westaby, D; Koh, D-M; Tunariu, N; Carreira, S; de Bono, JS; Fotiadis, N
BACKGROUND: Bone biopsies in metastatic castrate-resistant prostate cancer (mCRPC) patients can be challenging. This study's objective was to prospectively validate a multiparametric bone MRI (mpBMRI) algorithm to facilitate target lesion selection in mCRPC patients with sclerotic bone disease for subsequent CT-guided bone biopsies. METHODS: 20 CT-guided bone biopsies were prospectively performed between 02/2021 and 11/2021 in 17 mCRPC patients with only sclerotic bone disease. Biopsy targets were selected based on MRI, including diffusion-weighted (DWI) and T1-weighted VIBE Dixon MR images, allowing for calculation of the apparent diffusion coefficient (ADC) and the relative fat-fraction (rFF), respectively. Bone marrow with high DWI signal, ADC < 1100 µm2/s and rFF < 20% was the preferred biopsy target. Tumor content and NGS-feasibility was assessed by a pathologist. Prognostic routine laboratory blood parameters, target lesion size, biopsy tract length, visual CT density, means of HU, ADC and rFF were compared between successful and unsuccessful biopsies (p < 0.05 = significant). RESULTS: Overall, 17/20 (85%) biopsies were tumor-positive and next-generation genomic sequencing (NGS) was feasible in 13/18 (72%) evaluated samples. Neither laboratory parameters, diameter, tract length nor visual CT density grading showed significant differences between a positive versus negative or NGS feasible versus non-feasible biopsy results (each p > 0.137). Lesion mean HU was 387 ± 187 HU in NGS feasible and 493 ± 218 HU in non-feasible biopsies (p = 0.521). For targets fulfilling all MRI selection algorithm criteria, 13/14 (93%) biopsies were tumor-positive and 10/12 (83%) provided NGS adequate tissue. CONCLUSIONS: Multiparametric bone MRI can facilitate target lesion selection for subsequent CT-guided bone biopsy in mCPRC patients with sclerotic metastases. TRIAL REGISTRATION: Committee for Clinical Research of the Royal Marsden Hospital registration number SE1220.
2023-12-15T00:00:00ZDNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells.Hristova, DBOliveira, MWagner, EMelcher, AHarrington, KJBelot, AFerguson, BJhttps://repository.icr.ac.uk/handle/internal/61872024-03-15T09:16:08Z2024-01-19T00:00:00ZDNA-PKcs is required for cGAS/STING-dependent viral DNA sensing in human cells.
Hristova, DB; Oliveira, M; Wagner, E; Melcher, A; Harrington, KJ; Belot, A; Ferguson, BJ
To mount an efficient interferon response to virus infection, intracellular pattern recognition receptors (PRRs) sense viral nucleic acids and activate anti-viral gene transcription. The mechanisms by which intracellular DNA and DNA viruses are sensed are relevant not only to anti-viral innate immunity, but also to autoinflammation and anti-tumour immunity through the initiation of sterile inflammation by self-DNA recognition. The PRRs that directly sense and respond to viral or damaged self-DNA function by signaling to activate interferon regulatory factor (IRF)-dependent type one interferon (IFN-I) transcription. We and others have previously defined DNA-dependent protein kinase (DNA-PK) as an essential component of the DNA-dependent anti-viral innate immune system. Here, we show that DNA-PK is essential for cyclic GMP-AMP synthase (cGAS)- and stimulator of interferon genes (STING)-dependent IFN-I responses in human cells during stimulation with exogenous DNA and infection with DNA viruses.
2024-01-19T00:00:00ZInternational Survey on Frailty Assessment in Patients with Cancer.Banna, GLCantale, OHaydock, MMBattisti, NMLBambury, KMusolino, NO'Carroll, EMaltese, GGaretto, LAddeo, AGomes, Fhttps://repository.icr.ac.uk/handle/internal/61862024-03-15T09:16:02Z2022-10-01T00:00:00ZInternational Survey on Frailty Assessment in Patients with Cancer.
Banna, GL; Cantale, O; Haydock, MM; Battisti, NML; Bambury, K; Musolino, N; O'Carroll, E; Maltese, G; Garetto, L; Addeo, A; Gomes, F
BACKGROUND: Frailty negatively affects the outcomes of patients with cancer, and its assessment might vary widely in the real world. The objective of this study was to explore awareness and use of frailty screening tools among the ONCOassist healthcare professionals (HCPs) users. MATERIALS AND METHODS: We sent 2 emails with a cross-sectional 15-item survey in a 3-week interval between April and May 2021. Differences in the awareness and use of tools according to respondents' continents, country income, and job types were investigated. RESULTS: Seven hundred thirty-seven HCPs from 91 countries (81% physicians, 13% nurses, and 5% other HCPs) completed the survey. Three hundred and eighty-five (52%) reported assessing all or the majority of their patients; 518 (70%) at baseline and before starting a new treatment. Three hundred and four (43%) HCPs were aware of performance status (PS) scores only, 309 (42%) age/frailty/comorbidity (AFC) screening, and 102 (14%) chemotoxicity predictive tools. Five hundred and thirty-seven (73%) reported using tools; 423 (57%) just PS, 237 (32%) AFC, and 60 (8%) chemotoxicity ones. Reasons for tools non-use (485 responders) were awareness (70%), time constraints (28%), and uselessness (2%). There were significant differences in awareness and use of screening tools among different continents, country income, job types, and medical specialties (P < .001 for all comparisons). CONCLUSION: Among selected oncology HCPs, there is still a worldwide lack of knowledge and usage of frailty screening tools, which may differ according to their geography, country income, and education. Targeted initiatives to raise awareness and education are needed to implement frailty assessment in managing patients with cancer.
2022-10-01T00:00:00Z