Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

[Objective]: The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.[Design]: Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.[Results]: Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment.[Conclusion]: Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.JCL-G received support from a 'la Caixa' Foundation (ID 100010434) fellowship (LCF/BQ/DR21/11880011). This study was supported by ISCIII FIS grants PI18/00757 and PI21/01110 (BSJ) and PI18/00267 (LG-B), and grants from the Spanish Ministry of Economy and Innovation SAF2016-76504-R (ACan and FP), PID2019-111052RB-I00 (FP), PID2019-104644RB-I00 (GM-B), a Ramón y Cajal Merit Award RYC-2012–12104 (BSJ) and ISCIII, CIBERONC, CB16/12/00446 (ACar) and CB16/12/00295 (ACan and GM-B), all of them co-financed through Fondo Europeo de Desarrollo Regional (FEDER) 'Una manera de hacer Europa'; a Fero Foundation Grant (BSJ); a Coordinated grant (GC16173694BARB) from the Fundación Científica Asociación Española Contra el Cáncer (FC-AECC) (BSJ); a Miguel Servet award (CP16/00121) (PS); a DFG, German Research Foundation Grant—Project no: 492 436 553 (KG); and a Max Eder Fellowship of the German Cancer Aid (111746) (PCH

The reference site collaborative network of the european innovation partnership on active and healthy ageing

Seventy four Reference Sites of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) have been recognised by the European Commission in 2016 for their commitment to excellence in investing and scaling up innovative solutions for active and healthy ageing. The Reference Site Collaborative Network (RSCN) brings together the EIP on AHA Reference Sites awarded by the European Commission, and Candidate Reference Sites into a single forum. The overarching goals are to promote cooperation, share and transfer good practice and solutions in the development and scaling up of health and care strategies, policies and service delivery models, while at the same time supporting the action groups in their work. The RSCN aspires to be recognized by the EU Commission as the principal forum and authority representing all EIP on AHA Reference Sites. The RSCN will contribute to achieve the goals of the EIP on AHA by improving health and care outcomes for citizens across Europe, and the development of sustainable economic growth and the creation of jobs

Operative definition of active and healthy ageing (AHA): Meeting report. Montpellier October 20-21, 2014

The broad concept of Active and Healthy Ageing was proposed by WHO as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal active and healthy ageing definition is not available and may differ depending on the purpose of the definition and/or the questions raised. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact but a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc Roussillon). The goal of the meeting was to propose an operational definition of Active and Healthy Ageing as well as tools that may be used for this definition. The current paper provides a summary of the plenary presentations that were given during the meeting

Operative definition of active and healthy ageing (AHA): Meeting report. Montpellier October 20-21, 2014

The broad concept of Active and Healthy Ageing was proposed by WHO as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal active and healthy ageing definition is not available and may differ depending on the purpose of the definition and/or the questions raised. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact but a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc Roussillon). The goal of the meeting was to propose an operational definition of Active and Healthy Ageing as well as tools that may be used for this definition. The current paper provides a summary of the plenary presentations that were given during the meeting

Operative definition of active and healthy ageing (AHA): Meeting report. Montpellier October 20–21, 2014

International audienceThe broad concept of Active and Healthy Ageing was proposed by WHO as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal active and healthy ageing definition is not available and may differ depending on the purpose of the definition and/or the questions raised. The European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact but a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc Roussillon). The goal of the meeting was to propose an operational definition of Active and Healthy Ageing as well as tools that may be used for this definition. The current paper provides a summary of the plenary presentations that were given during the meeting

Operational definition of Active and Healthy Ageing (AHA): A conceptual framework

International audienceHealth is a multi-dimensional concept, capturing how people feel and function. The broad concept of Active and Healthy Ageing was proposed by the World Health Organisation (WHO) as the process of optimizing opportunities for health to enhance quality of life as people age. It applies to both individuals and population groups. A universal Active and Healthy Ageing definition is not available and it may differ depending on the purpose of the definition and/or the questions raised. While the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) has had a major impact, a definition of Active and Healthy Ageing is urgently needed. A meeting was organised in Montpellier, France, October 20-21, 2014 as the annual conference of the EIP on AHA Reference Site MACVIA-LR (Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc Roussillon) to propose an operational definition of Active and Healthy Ageing including tools that may be used for this. The current paper describes the rationale and the process by which the aims of the meeting will be reached

Operational Definition of Active and Healthy Aging (AHA): The European Innovation Partnership (EIP) on AHA Reference Site Questionnaire: Montpellier October 20-21, 2014, Lisbon July 2, 2015

A core operational definition of active and healthy aging (AHA) is needed to conduct comparisons. A conceptual AHA framework proposed by the European Innovation Partnership on Active and Healthy Ageing Reference Site Network includes several items such as functioning (individual capability and underlying body systems), well-being, activities and participation, and diseases (including noncommunicable diseases, frailty, mental and oral health disorders). The instruments proposed to assess the conceptual framework of AHA have common applicability and availability attributes. The approach includes core and optional domains/instruments depending on the needs and the questions. A major common domain is function, as measured by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). WHODAS 2.0 can be used across all diseases and healthy individuals. It covers many of the AHA dimensions proposed by the Reference Site network. However, WHODAS 2.0 does not include all dimensions proposed for AHA assessment. The second common domain is health-related quality of life (HRQoL). A report of the AHA questionnaire in the form of a spider net has been proposed to facilitate usual comparisons across individuals and groups of interest