Open Questions for Harnessing Autophagy-Modulating Drugs in the SARS-CoV-2 War

New article in Autophagy

From : Brest P, Benzaquen J, J.Klionsky D, Hofman P, Mograbi B.

2020 APRIL 3 ;1 : 0022


At a time when the world faces an emotional breakdown, crushing our dreams if not taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined to home. Every day, like everyone else, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One of the most recent has drawn worldwide hype to the possible benefit of chloroquine (CQ), a well-known and broadly used anti-malarial drug, in the treatment of patients infected by the recently emerged deadly coronavirus (SARS-CoV-2). We should consider this information in the light of the long-standing anti-inflammatory and anti-viral properties of CQ-related drugs. Yet, none of these articles evoked a possible molecular or cellular mechanism of action that could account for any efficacy. Here, given the interaction of viruses with macroautophagy (hereafter referred to as autophagy), a CQ-sensitive anti-viral safeguard pathway, we would like to discuss some pros and cons concerning the current therapeutic options targeting this process.

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Editorial m/s – Un objectif de santé publique : le vieillissement durable

Editorial dans medecine/sciences 2020, par Eric GILSON

Un objectif de santé publique : le vieillissement durable

Le vieillissement est généralement vu par les biologistes comme une diminution progressive de la fonctionnalité des organes, pou- vant aboutir à la mort. Il s’accompagne d’une augmentation de la susceptibilité de développer de nombreux cancers et maladies dégénératives pouvant toucher la quasi-totalité des organes (maladies neurodégénératives, cardio-vasculaires, métabo- liques, pulmonaires et articulaires pour n’en citer que quelques unes). Savoir si le vieillissement est un processus programmé, comme l’est le développement, dont il pourrait constituer l’épi- logue, ou simplement une accumulation aléatoire de dommages est une question polémique. En d’autres termes, existe-t-il une biologie propre du vieillissement ou simplement des situations physiopathologiques liées à la dégénérescence des organes et des systèmes ? Cette question est fondamentale…

Article complet ms edito

Mini Symposium “Update in Lung Cancer Biomarkers”, December, 6th, 2019

Pr. Benjamin Besse

The FHU Oncoage had the pleasure to welcome several world leading experts for the Mini Symposium “Update in Lung Cancer Biomarkers” providing novel insights on the development of biomarkers in Lung Cancer.


Dr. Catherine Alix-Panabières

Pr. Benjamin Besse, Head of the Thoracic Oncology Unit at Gustave Roussy Cancer in Paris and chair of the EORTC Lung Cancer Group provided a fascinating insight on the role of Radon in Lung Cancer development, followed by an intriguing presentation by Dr. Catherine Alix-Panabières, Director of the Laboratory Rare Circulating Human Cells at the CHU of Montpellier, about the importance of circulating tumor cells. The symposium was concluded by Prof. Angel Märten, Global Medical Advisor at Boehringer Ingelheim presenting great work about the importance of uncommon EGFR mutations in lung Cancer and Prof. Albrecht Stenzinger, Head of the IPH Center for Molecular Pathology who highlighted the importance of biomarker development for anti-cancer immunotherapy.


The symposium was concluded by the thesis defense of Simon Heeke, PhD candidate in the team of Pr. Paul Hofman, Director of the FHU Oncoage.

From left to right : Prof. Angel Märten, Prof. Albrecht Stenzinger, Dr. Nathalie Mazure, Pr. Paul Hofman, Dr. Catherine Alix-Panabières, Pr. Benjamin Besse


Mini workshop on Lung Cancer – Nice, 11-8-19

Friday, November 8, 2019 was held the 2nd OncoAge workshop on lung cancer “Lung Cancer Physiopathology”, with the participation of speakers from the Leon Berard Cancer Center (Lyon), the Mediterranean Center of Molecular Medicine (C3M, Nice) and the Institute for Research on Cancer and Aging, Nice (IRCAN, Nice).

A high-level working session, several collaborations between the different teams are in perspective, to be continued


Speakers and participants of OncoAge workshop at Saint Paul Hotel, in Nice


Léa Berland testimonial : internship at the MD Anderson Cancer Center in Houston

As a student in dual curriculum (medical and scientific studies) at the Faculty of Medicine of Nice and at the INSERM Liliane Bettencourt School, I had the opportunity to carry out two research internships. My first choice was Professor Hofman’s laboratory without hesitation. I was able to discover their projects during the courses of the Master Biopathology directed by Pr Ilié at the Faculty of Medicine, and I was immediately enthusiastic about the interest and quality of the research conducted in their laboratory. Professor Ilié became my mentor in the laboratory and introduced me to the world of research.

At the Laboratory of Clinical and Experimental Pathology (LPCE), I learned the essential skills that allow me to thrive in my new projects today. Indeed, thanks to Professor Hofman’s help and recommendations, I am currently doing my internship at the MD ANDERSON CANCER CENTER in Houston (USA). I am fortunate to be able to work with Professor Calin’s team on the role played by microRNAs and other non-coding RNAs in the development of cancers.

During my internship at the LPCE, having worked on a project to evaluate the response of lung cancer patients to immunotherapy, I quickly realized the importance of this area in the future management of patients. So I decided, as of the beginning of the next academic year, to integrate the Master 2 Immunology at the Pierre and Marie Curie University (Paris, France), as well as the Pasteur “Advanced Immunology” courses. My research internship will take place at Dana Farber Cancer Center in Boston, USA.

I thank Professor Hofman, Professor Ilié and all the members of the LPCE for sharing their passion for research with me and for allowing me to seize such great opportunities. My transition to the LPCE has made me mature from both a scientific and a human point of view.

George CALIN’s team with Léa BERLAND

Sunset in front of the laboratory

Discovering the cellular landscape of the airways and the lung

Nice University Hospital is one of the 15 partners of the DiscovAIR project (“Discovering the cellular landscape of the airways and the lung”) which has just been accepted within the framework of the H2020 calls for projects. In collaboration with the both CNRS team of the IPMC of Sophia Antipolis (Pr Pascal Barbry) and FHU ONCOAGE members at Nice Hospital (Dr Sylvie Leroy  and Pr Charles Hugo Marquette, Pneumology Department; Pr Paul Hofman, LPCE) we are the only french representatives of this European consortium (see list below).


The Lung Cell Atlas: a novel approach to face the huge burden of lung disease

Lung disease is a leading cause of death worldwide1, with incidence increasing at an alarming rate while curative interventions are lacking. Research into lung disease lags behind compared to cancer and cardiovascular disease, the other 2 major causes of death2. One reason for this may be the high complexity of the lung, with at least 40 different cell types organised in a complex, three-dimensional structure. Hence, there is an urgent need to grasp this complexity and propel basic, translational and clinical research in lung disease into a fast-track for the development of precision diagnostics and therapeutics. To achieve this, a detailed understanding is required of the cells that make up the lung, their fixed and variable features, their interactions and their organization into macroscopic tissue architecture in health and disease. DiscovAIR will establish the first draft of the Human Lung Cell Atlas, focusing on healthy lung, but including small disease cohorts, enabling accelerated translational and clinical research into lung disease. The discovAIR results will facilitate progress in regenerative and precision medicine and identify novel candidates for precision diagnostics and curative interventions in lung disease for the diagnostic and pharmacological industry, thereby contributing to healthy ageing and active living in Europe.

DiscovAIR: a foundation for integrated mapping of molecular state and spatial location of single cells

Recent progress in multimodal molecular profiling of single cells has allowed discovAIR partners to draft the first cellular census of healthy human lung3, and to describe the alterations in molecular states and relative frequencies of cells in the airway wall in asthma. In this work, we identified novel, disease-relevant cell states, such as mucous- producing ciliated cells, and confirmed novel cell types, such as the ionocyte – a newly discovered cell type highly expressing CFTR, the cystic fibrosis gene4. We also chart a radically changed intercellular communication network in disease, revealing a wealth of novel interactions specific to the asthmatic airway wall, that need to be tested for diagnostic and therapeutic applications. We now need to chart the cellular makeup of the lung at higher resolution, sampling more locations along the bronchial tree and in the parenchyma. In particular, we need to map lung cells onto the tissue architecture, chart the local cellular neighbourhoods and their alterations in a wider range of diseases, and identify their molecular fingerprints. This will guide the identification of the processes driving disease inception, progression and exacerbation as well as the development of novel diagnostic and therapeutic approaches.

DiscovAIR will move beyond the current state of the art by combining multimodal profiling of lung tissue cells with a detailed spatial mapping of the identified cell states, 3D reconstruction of lung tissue architecture from transcriptionally defined cell states, in-depth molecular phenotyping of local cellular neighbourhoods and development of novel computational approaches to integrate the multimodal data of the spatial and the cellular branches of discovAIR.

First draft of the Lung Cell Atlas: delivering a blueprint for the Human Cell Atlas

The lung is a complex and highly structured organ, containing an extensive variety of cell types. Molecular phenotypes of lung cells are determined by their role in maintaining physical and immunological barrier functions or facilitating gas exchange, as well as by their location within the tissue architecture. Importantly, healthy lung tissue is available to a large number of research groups through bronchoscopy programs involving healthy volunteers and patients with lung disease, and from lung transplantation and resection programs. This combination of a highly ordered tissue architecture – facilitating the implementation of a common coordinate framework – and good community-wide availability of tissue makes lung especially well-suited as a lead organ for the HCA to develop the infrastructure, workflows and platforms needed for a community-driven mapping effort as laid down in the vision of the Human Cell Atlas consortium5. Consequently, atlases of both the airways and parenchymal lung tissue have been selected by the HCA consortium as a priority effort, with the potential for the Lung Cell Atlas to grow into one of the HCA Flagship projects6. The infrastructure, workflows and platforms developed by discovAIR – rooted within the HCA Lung working group – will serve as blueprints within the HCA community. Best practices and lessons learned from the Human Lung Cell Atlas delivered by the discovAIR project will empower the HCA to achieve its ambition of charting every cell in the healthy human body.

The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress

New article in Nature Oncogene Journal

Laura Moreno Leon, Marine Gautier, Richard Allan, Marius Ilié, Nicolas Nottet, Nicolas Pons, Agnes Paquet, Kévin Lebrigand, Marin Truchi, Julien Fassy, Virginie Magnone, Garrett Kinnebrew, Milan Radovich, Meyling Hua-Chen Cheok, Pascal Barbry, Georges Vassaux, Charles-Hugo Marquette, Gilles Ponzio, Mircea Ivan, Nicolas Pottier, Paul Hofman, Bernard Mari & Roger Rezzonico


Lung cancer is the leading cause of cancer death worldwide, with poor prognosis and a high rate of recurrence despite early surgical removal. Hypoxic regions within tumors represent sources of aggressiveness and resistance to therapy. Although long non-coding RNAs (lncRNAs) are increasingly recognized as major gene expression regulators, their regulation and function following hypoxic stress are still largely unexplored. Combining profiling studies on early-stage lung adenocarcinoma (LUAD) biopsies and on A549 LUAD cell lines cultured in normoxic or hypoxic conditions, we identified a subset of lncRNAs that are both correlated with the hypoxic status of tumors and regulated by hypoxia in vitro.
We focused on a new transcript, NLUCAT1, which is strongly upregulated by hypoxia in vitro and correlated with hypoxic markers and poor prognosis in LUADs. Full molecular characterization showed that NLUCAT1 is a large nuclear transcript composed of six exons and mainly regulated by NF-κB and NRF2 transcription factors. CRISPR-Cas9-mediated invalidation of NLUCAT1 revealed a decrease in proliferative and invasive properties, an increase in oxidative stress and a higher sensitivity to cisplatin-induced apoptosis. Transcriptome analysis of NLUCAT1-deficient cells showed repressed genes within the antioxidant and/or cisplatin-response networks. We demonstrated that the concomitant knockdown of four of these genes products, GPX2, GLRX, ALDH3A1, and PDK4, significantly increased ROS-dependent caspase activation, thus partially mimicking the consequences of NLUCAT1 inactivation in LUAD cells. Overall, we demonstrate that NLUCAT1 contributes to an aggressive phenotype in early-stage hypoxic tumors, suggesting it may represent a new potential therapeutic target in LUADs.

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In-House Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-Small Cell Lung Cancer and Melanoma Patients



Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC.

Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no di erences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.

Want to see the full article: cancers-11-01271-v2

Want to see the videos


Appointment of Prof. Sabrina Sacconi, she will head the research axis dedicated to neurodegenerative and neuromuscular disorders

Short biography of Sabrina Sacconi PU PH

Professor of Neurology and works at the University Hospital of Nice as Head of the Peripheral Nervous System and Muscle Department, Head of the Rare Neuromuscular Diseases Reference Centre and the Competence Centre for Neurogenetic Diseases. She is also a researcher at IRCAN (Institut of Research on Cancer and Aging of Nice, INSERM U1081 – CNRS UMR 7284) directed by Professor Eric GILSON. Very active in research, both in the clinical and fundamental aspects, she obtained a PhD in Science from UNSA in 2008 and an Habilitation to Lead Research in 2012. His main research interests are Facio-Scapulo-Humeral Muscular Dystrophy and degenerative muscle diseases, with a particular focus on the impact of ageing and genomic instability on the pathophysiology of these rare diseases, as well as on the possible impact on innovative therapies. She is also interested in the use of new technologies to improve the diagnosis and clinical evaluation of neuromuscular diseases.

Interview of Sabrina Sacconi:

  • What research, innovations or major advances in knowledge are you currently focusing on?

Thanks to advances in new technologies, innovative immunological and gene therapies in the field of neuromuscular and neurodegenerative diseases are making major advances and are beginning to be tested and used on patients.

Faced with these new opportunities, many clinical and biological questions arise as to how to develop new therapies that are more effective or less toxic, how to identify and select patients who could benefit from them, how to quantify the biological effects in the short and long term, and what strategy to adopt in more advanced disease stages. 

These therapies could also be applicable to the aging of muscles and brains and furthering knowledge about normal aging and pathological aging in these two tissues could lead to the development of more therapies for neuromuscular and neurodegenerative diseases and all diseases related to aging.

  • You are currently working on many research projects, can you tell us a few words about them? Do you have any other plans for the future?
The research projects I am working on answer the questions raised above. Currently I am working on the constitution of cohorts that integrate new digital technologies for data collection, sample storage in bio-banks to stimulate translational research and artificial intelligence for statistical analysis and the creation of mathematical models (RESOLVE International Project, French National Observatory DMFSH).
Using new digital technologies, in vitro and in vivo models of normal and pathological aging, we are developing and testing new therapeutic strategies (such as immunotherapies for patients with neuromuscular genetic diseases), new indicators for measuring the progression of a disease or the effectiveness of a therapeutic approach (FACE NMD project, RESOLVE France, SMA2T) applicable at a distance (ALCOTRA PROSOL European Project, PROSOLCARE telemedicine platform) or biomarkers of severity or therapeutic monitoring in the field of neuromuscular diseases (FSHD CYTO) and ageing. For the future, I would like to continue and expand these projects and promote collaborations with the teams investing in fundamental and translational research within OncoAge and with the clinical teams within the OPTIMAGE Consortium.
  • Can the federation be a support to help you progress through the network it leads?
Most of the projects I am working on are the result of collaborations promoted within the ONCOAGE Federation with research teams from IRCAN and CHUN, of which I am a member, but also from INRIA, IPMC and ICP. The transversal and multidisciplinary approach and the sharing of human and technological resources have made it possible to progress more quickly in the construction of projects. The support for dissemination and training through logistical support for the organization of congresses made it possible to organize within ONCOAGE the first European congress on e-health and innovation in the field of neuromuscular diseases « eNMD 2019: e-health and innovation to overcome barriers in NMD ».  
  • Your willingness for this working group as a Work Package Leader?
Within OncoAge, I intend to federate, the research and fundamental teams involved in the field of neuromuscular and neurodegenerative diseases around concrete objectives, decided in a collegial manner; while benefiting from and developing new technologies and innovative therapeutic approaches in the field of normal and pathological ageing of the brain and muscle.