New project : Post-transcriptional plasticity in cellular adaptation to tumorigenesis and chemoresistance: new models and tools

Post-transcriptional plasticity in cellular adaptation to tumorigenesis and chemoresistance: new models and tools

  • Funding: INCA
  • Partnership : IRCAN & IBV
  • Duration : 3 years

ABSTRACT
Small Cell Lung Cancers (SCLC) are fast evolving tumors, characterized by rapid growth, quick metastasis, and despite sensitivity to initial systemic cytotoxic  chemotherapy, SCLCs quickly develop chemotherapy resistance. Although mRNA translation control is critical to the rapid adaptation of gene expression to stress, its contribution to cellular survival and chemoresistance in the tumor microenvironment remains to be established.
Translationally repressed mRNAs are stored in P-bodies and are of particular relevance to study tumorigenesis because they control cell proliferation, differentiation, and resistance to stress, and they can be quickly mobilized to adapt gene expression to cellular needs. In addition, deregulation of the expression of P-body components is a signature of SCLC as revealed by our recent analysis. In the model organism C. elegans, disruption of P-body regulatory components induces tumorigenesis. Here, using these two complementary models, SCLC spheroids and induced C. elegans tumors, we will assess how alterations in P-body post-transcriptional pathways participate to tumorigenesis and stress resistance.

We aim to: (1) identify post-transcriptional signatures of SCLC tumors and oxidative stress resistance, (2) dissect how these post-transcriptional regulations participate to resistance in a tumor context, and (3) develop candidate and screen approaches to target P-body remodeling in tumors. By developing cutting edge sequencing methods and adapting two complementary models, we will provide a comprehensive and mechanistic view of the plasticity of RNA translation control during tumorogenesis and in response to oxidative stress using an approach distinct from the classical methods used to identify transcriptional signatures.

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

New article in Preprints

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

2020 APRIL 3 ;1 : 0022

ABSTACT

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.

Full article

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

Abstract: 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.

See the full article

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

cancers

Abstract: 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

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