Editorial: How Do Metabolism, Angiogenesis, and Hypoxia Modulate Resistance?

Resistència al càncer; Cèl·lules mare cancerígenes; TeràpiaResistencia al cáncer; Células madre cancerosas; TerapiaCancer resistance; Cancer stem cell; TherapyMetabolic alterations were among the first discovered hallmarks of cancer. They were first described 90 years ago when Otto Warburg realized that cancer cells in culture had a relatively increased metabolic rate (the Warburg hypothesis). It has been proposed that the drastic changes seen in cancer metabolism are in part attributed to mutations in the mtDNA, metabolic reprogramming, or mitochondrial dysfunction. However, novel players in cancer metabolism are emerging.This work was supported by ISCIII (Instituto de Salud Carlos III) Ref. FIS PI15/01262 (MELL), co-financed by the European Regional Development Fund (ERDF) and AECC Project GEC Ref. GC16173720CARR (MELL)

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

B-cell lymphoma; Cancer geneticsLinfoma de células B; Genética del cáncerLimfoma de cèl·lules B; Genètica del càncerPlasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.Open Access funding enabled and organized by Projekt DEAL

DigiPatICS: Digital Pathology Transformation of the Catalan Health Institute Network of 8 Hospitals—Planification, Implementation, and Preliminary Results

Artificial intelligence; Digital pathology; ImplementationInteligencia artificial; Patología digital; ImplementaciónIntel·ligència artificial; Patologia digital; ImplementacióComplete digital pathology transformation for primary histopathological diagnosis is a challenging yet rewarding endeavor. Its advantages are clear with more efficient workflows, but there are many technical and functional difficulties to be faced. The Catalan Health Institute (ICS) has started its DigiPatICS project, aiming to deploy digital pathology in an integrative, holistic, and comprehensive way within a network of 8 hospitals, over 168 pathologists, and over 1 million slides each year. We describe the bidding process and the careful planning that was required, followed by swift implementation in stages. The purpose of the DigiPatICS project is to increase patient safety and quality of care, improving diagnosis and the efficiency of processes in the pathological anatomy departments of the ICS through process improvement, digital pathology, and artificial intelligence tools.This project was funded by European Regional Development Funds, Programa operatiu FEDER de Catalunya 2014–2020 and SA18-014623 DIGIPATICS. UPC activity in this project was partially supported by PID2020-116907RB-I00 and funded by MCIN/AEI/10.13039/501100011033

Clinical and pathological characteristics of peripheral T-cell lymphomas in a Spanish population: a retrospective study

Anaplastic large-cell lymphoma; Progression-free survivalLinfoma anaplásico de células grandes; Supervivencia libre de progresiónLimfoma anaplàsic de cèl·lules grans; Supervivència lliure de progressióWe investigated the clinicopathological features and prognostic factors of patients with peripheral T-cell lymphoma (PTCL) in 13 sites across Spain. Relevant clinical antecedents, CD30 expression and staining pattern, prognostic indices using the International Prognostic Index and the Intergruppo Italiano Linfomi system, treatments, and clinical outcomes were examined. A sizeable proportion of 175 patients had a history of immune-related disorders (autoimmune 16%, viral infections 17%, chemo/radiotherapy-treated carcinomas 19%). The median progression-free survival (PFS) and overall survival (OS) were 7·9 and 15·8 months, respectively. Prognostic indices influenced PFS and OS, with a higher number of adverse factors resulting in shorter survival (P 15% of cells were positive in anaplastic lymphoma kinase-positive and -negative anaplastic large-cell lymphoma and extranodal natural killer PTCL groups. We observed PTCL distribution across subtypes based on haematopathological re-evaluation. Poor prognosis, effect of specific prognostic indices, relevance of histopathological sub-classification, and response level to first-line treatment on outcomes were confirmed. Immune disorders amongst patients require further examination involving genetic studies and identification of associated immunosuppressive factors.This study was sponsored by Takeda

Detection of early seeding of Richter transformation in chronic lymphocytic leukemia

B-cell lymphoma; Cancer epigenetics; Chronic lymphocytic leukaemiaLinfoma de células b; Epigenética del cáncer; Leucemia linfocítica crónicaLimfoma de cèl·lules b; Epigenètica del càncer; Leucèmia limfocítica crònicaRichter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high–B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.The authors thank the Hematopathology Collection registered at the Biobank of Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and the Biobank HUB-ICO-IDIBELL (PT20/00171) for sample procurement, S. Martín, F. Arenas, the Genomics Core Facility of the IDIBAPS, CNAG Sequencing Unit, Mission Bio, Omniscope and Barcelona Supercomputing Center for the technical support and the computer resources at MareNostrum4 (RES activity, BCV-2018-3-0001). This study was supported by the la Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221, to E.C.), the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (810287, BCLLatlas, to E.C., J.I.M.-S., H.H. and I.G.), the Instituto de Salud Carlos III and the European Regional Development Fund Una Manera de Hacer Europa (PMP15/00007 to E.C. and RTI2018-094584-B-I00 to D.C.), the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE to F.N.), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245 to F.N.), the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223 to F.N.), the Generalitat de Catalunya Suport Grups de Recerca AGAUR (2017-SGR-1142 to E.C., 2017-SGR-736 to J.I.M.-S. and 2017-SGR-1009 to D.C.), the Accelerator award CRUK/AIRC/AECC joint funder partnership (AECC_AA17_SUBERO to J.I.M.-S.), the Fundació La Marató de TV3 (201924-30 to J.I.M.-S.), the Centro de Investigación Biomédica en Red Cáncer (CIBERONC; CB16/12/00225, CB16/12/00334, CB16/12/00236), the Ministerio de Ciencia e Innovación (PID2020-117185RB-I00 to X.S.P.), the Fundación Asociación Española Contra el Cáncer (FUNCAR-PRYGN211258SUÁR to X.S.P.), the Associazione Italiana per la Ricerca sul Cancro Foundation (AIRC 5 × 1,000 no. 21198 to G.G.) and the CERCA Programme/Generalitat de Catalunya. H.P.-A. is a recipient of a predoctoral fellowship from the Spanish Ministry of Science, Innovation and Universities (FPU19/03110). A.D.-N. is supported by the Department of Education of the Basque Government (PRE_2017_1_0100). E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. This work was partially developed at the Center Esther Koplowitz (Barcelona, Spain)

SDCBP Modulates Stemness and Chemoresistance in Head and Neck Squamous Cell Carcinoma through Src Activation

Cèl·lules mare del càncer; QuimioresistènciaCélulas madre del cáncer; QuimiorresistenciaCancer stem cells; ChemoresistanceTo characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.This research was supported by grants from the Instituto de Salud Carlos III (ISCIII): PI15/01262 and CP03/00101 (M.E.LL.), PI19/00560 (J.G.-P.), and CIBERONC (M.E.LL. and IDI2018/155 J.P.R.) and was co-financed by the European Regional Fund (ERDF) and AECC (Spanish Association of Cancer Research) Founding Ref. GC16173720CARR (M.E.LL.). Y.G.M. and C.M. were supported by the VHIR and iP-FIS (ISCIII) fellowships, respectively. We acknowledge the Principado de Asturias BioBank (PT17/0015/0023)

DigiPatICS: Digital Pathology Transformation of the Catalan Health Institute Network of 8 hospitals—planification, implementation, and preliminary results

Complete digital pathology transformation for primary histopathological diagnosis is a challenging yet rewarding endeavor. Its advantages are clear with more efficient workflows, but there are many technical and functional difficulties to be faced. The Catalan Health Institute (ICS) has started its DigiPatICS project, aiming to deploy digital pathology in an integrative, holistic, and comprehensive way within a network of 8 hospitals, over 168 pathologists, and over 1 million slides each year. We describe the bidding process and the careful planning that was required, followed by swift implementation in stages. The purpose of the DigiPatICS project is to increase patient safety and quality of care, improving diagnosis and the efficiency of processes in the pathological anatomy departments of the ICS through process improvement, digital pathology, and artificial intelligence tools.This project was funded by European Regional Development Funds, Programa operatiu FEDER de Catalunya 2014–2020 and SA18-014623 DIGIPATICS. UPC activity in this project was partially supported by PID2020-116907RB-I00 and funded by MCIN/AEI/10.13039/501100011033Peer ReviewedArticle signat per 18 autors/es: Jordi Temprana-Salvador (1), Pablo López-García (2), Josep Castellví Vives (1),Lluís de Haro (2), Eudald Ballesta (2), Matias Rojas Abusleme (3), Miquel Arrufat (4), Ferran Marques (5), Josep R. Casas (5),Carlos Gallego (6), Laura Pons (7), José Luis Mate (7), Pedro Luis Fernández (7), Eugeni López-Bonet (8), Ramon Bosch (9), Salomé Martínez (10), Santiago Ramón y Cajal (1), and Xavier Matias-Guiu (11,12) // (1) Department of Pathology, Vall d’Hebron University Hospital, CIBERONC, 08035 Barcelona, Spain; (2) Functional Competence Center, Information Systems, Catalan Health Institute (Institut Català de la Salut), 08006 Barcelona, Spain; (3) Center for Telecommunications and Information Technology (Centre de Telecomunicacions i Tecnologies de la Informació, CTTI), Catalan Health Institute (Institut Català de la Salut), 08006 Barcelona, Spain; (4) Economic and Financial Management, Catalan Health Institute (Institut Català de la Salut), 08006 Barcelona, Spain; (5) Image Processing Group, Technical University of Catalonia (UPC), 08034 Barcelona, Spain; (6) Digital Medical Imaging System of Catalonia (SIMDCAT), TIC Salut, 08005 Barcelona, Spain, (7) Department of Pathology, Germans Trias i Pujol University Hospital, 08916 Badalona, Spain; (8) Department of Pathology, Doctor Josep Trueta Hospital of Girona, 17007 Girona, Spain; (9) Department of Pathology, Verge de la Cinta Hospital of Tortosa, 43500 Tarragona, Spain; (10) Department of Pathology, Joan XXIII University Hospital of Tarragona, 43005 Tarragona, Spain; (11) Department of Pathology, Arnau de Vilanova University Hospital, 25198 Lleida, Spain, (12) Department of Pathology, Bellvitge University Hospital, CIBERONC, 08907 Barcelona, SpainPostprint (published version

BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling

Ovarian cancer; ProteomicsCáncer de ovarios: ProteómicaCàncer d'ovaris; ProteòmicaDespite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis. In addition, we identify key bridging proteins, kinase activity, and post-translational modifications responsible for molding distinct cancer phenotypes, thus providing new opportunities for therapeutic intervention, and ultimately advance towards a more personalized patient care.This work was supported by the PhD4MD collaborative research program between the Vall d’Hebron Research Institute (VHIR) and the Centre for Genomic Regulation (CRG). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I+D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, (CTQ2016-80364-P and “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208), and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595 and 2017SGR1661). This project has also received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC-XS). It has also been supported by grants from the Instituto Carlos III (PI15/00238, PI18/01017, PI21/00977), the Miguel Servet Program (CP13/00158 and CPII18/00027) and the Ministerio de Economía y Competitividad y Fondos FEDER (RTC-2015-3821-1). The authors are grateful to the team members of the Proteomics Unit at the Centre for Genomic Regulation, the Biomedical Research Group in Gynecology at the Vall d’Hebron Institute, the Gynecological Oncology Unit at the Vall d’Hebron Hospital and the Biomedical Research Group in Urology at the Vall d’Hebron Institute for their assistance

A combination of molecular and clinical parameters provides a new strategy for high-grade serous ovarian cancer patient management

Biomarker; Prediction; ProteomicsBiomarcador; Predicción; ProteómicaBiomarcador; Predicció; ProteòmicaBackground High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. Although most patients will initially respond to first-line treatment with a combination of surgery and platinum-based chemotherapy, up to a quarter will be resistant to treatment. We aimed to identify a new strategy to improve HGSC patient management at the time of cancer diagnosis (HGSC-1LTR). Methods A total of 109 ready-available formalin-fixed paraffin-embedded HGSC tissues obtained at the time of HGSC diagnosis were selected for proteomic analysis. Clinical data, treatment approach and outcomes were collected for all patients. An initial discovery cohort (n = 21) were divided into chemoresistant and chemosensitive groups and evaluated using discovery mass-spectrometry (MS)-based proteomics. Proteins showing differential abundance between groups were verified in a verification cohort (n = 88) using targeted MS-based proteomics. A logistic regression model was used to select those proteins able to correctly classify patients into chemoresistant and chemosensitive. The classification performance of the protein and clinical data combinations were assessed through the generation of receiver operating characteristic (ROC) curves. Results Using the HGSC-1LTR strategy we have identified a molecular signature (TKT, LAMC1 and FUCO) that combined with ready available clinical data (patients’ age, menopausal status, serum CA125 levels, and treatment approach) is able to predict patient response to first-line treatment with an AUC: 0.82 (95% CI 0.72–0.92). Conclusions We have established a new strategy that combines molecular and clinical parameters to predict the response to first-line treatment in HGSC patients (HGSC-1LTR). This strategy can allow the identification of chemoresistance at the time of diagnosis providing the optimization of therapeutic decision making and the evaluation of alternative treatment strategies. Thus, advancing towards the improvement of patient outcome and the individualization of HGSC patients’ care.This work was supported by the PhD4MD collaborative research program between the Vall d’Hebron Research Institute (VHIR) and the Centre for Genomic Regulation (CRG). It has been supported by grants from the Instituto Carlos III (PI18/01017), the Miguel Servet Program (CPII18/00027) and the Ministerio de Economía y Competitividad y Fondos FEDER (RTC-2015-3821-1 to AS and CTQ2016-80364-P to ES). This project has also received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC-XS).The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is supported by “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595 and 2017SGR1661). We also acknowledge support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme / Generalitat de Catalunya

Dendritic Cells From the Cervical Mucosa Capture and Transfer HIV-1 via Siglec-1

HIV-1; Siglec-1; CervixVIH-1; Siglec-1; CèrvixVIH-1; Siglec-1; CérvixAntigen presenting cells from the cervical mucosa are thought to amplify incoming HIV-1 and spread infection systemically without being productively infected. Yet, the molecular mechanism at the cervical mucosa underlying this viral transmission pathway remains unknown. Here we identified a subset of HLA-DR+ CD14+ CD11c+ cervical DCs at the lamina propria of the ectocervix and the endocervix that expressed the type-I interferon inducible lectin Siglec-1 (CD169), which promoted viral uptake. In the cervical biopsy of a viremic HIV-1+ patient, Siglec-1+ cells harbored HIV-1-containing compartments, demonstrating that in vivo, these cells trap viruses. Ex vivo, a type-I interferon antiviral environment enhanced viral capture and trans-infection via Siglec-1. Nonetheless, HIV-1 transfer via cervical DCs was effectively prevented with antibodies against Siglec-1. Our findings contribute to decipher how cervical DCs may boost HIV-1 replication and promote systemic viral spread from the cervical mucosa, and highlight the importance of including inhibitors against Siglec-1 in microbicidal strategies