Genetic changes in human pluripotent stem cells: implications for basic biology and regenerative medicine

Chronic tissue and organ failure caused by an injury, disease, ageing or congenital defects represents some of the most complex therapeutic challenges and poses a significant financial healthcare burden. Regenerative medicine strategies aim to fulfil the unmet clinical need by restoring the normal tissue function either through stimulating the endogenous tissue repair or by using transplantation strategies to replace the missing or defective cells. Stem cells represent an essential pillar of regenerative medicine efforts as they provide a source of progenitors or differentiated cells for use in cell replacement therapies. Whilst significant leaps have been made in controlling the stem cell fates and differentiating them to cell types of interest, transitioning bespoke cellular products from an academic environment to off-the-shelf clinical treatments brings about a whole new set of challenges which encompass manufacturing, regulatory and funding issues. Notwithstanding the need to resolve such issues before cell replacement therapies can benefit global healthcare, mounting progress in the field has highlighted regenerative medicine as a realistic prospect for treating some of the previously incurable conditions

Soft extracellular matrix drives an endoplasmic reticulum stress-dependent S quiescence underlying molecular traits of pulmonary basal cells

International audienc

Modelling cancer metabolism in vitro : current improvements and future challenges

International audienceAdvances in cancer biology over the past decades have revealed that metabolic adaptation of cancer cells is an essential aspect of tumorigenesis. However, recent insights into tumour metabolism in vivo have revealed dissimilarities with results obtained in vitro. This is partly due to the reductionism of in vitro cancer models that struggle to reproduce the complexity of tumour tissues. This review describes some of the discrepancies in cancer cell metabolism between in vitro and in vivo conditions, and presents current methodological approaches and tools used to bridge the gap with the clinically relevant microenvironment. As such, these approaches should generate new knowledge that could be more effectively translated into therapeutic opportunities

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

International audienceThe kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD+ for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD+ also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success

Cellular adaptation to amino acid availability: mechanisms involved in the regulation of gene expression

International audienceIn mammals, the impact of nutrients on gene expression has become an important area of research. Nevertheless, the current understanding of amino acid-dependent control of gene expression is limited. Amino acids have multiple and important roles, so their homeostasis has to be finely maintained. However, the blood amino acid content can be affected by certain nutritional conditions or various forms of pathology. It follows that mammals have to adjust several of their physiological functions involved in the adaptation to amino acid availability by regulating expression of numerous genes. The aim of this review is to examine the role of amino acids in regulating mammalian gene expression and physiological functions. A limitation for several individual amino acids strongly increases the expression of target genes such as insulin-like growth factor-binding protein1 (IGFBP-1), C/EBP homologous protein (CHOP) and asparagine synthetase (ASNS) genes. The molecular mechanisms involved in the regulation of CHOP and ASNS gene transcription in response to amino acid starvation have been partly identified. In particular, a signalling pathway requiring the protein kinase general control non-derepressive 2 (GCN2) and the activating transcription factor 4 (ATF4) has been described as sensing the amino acid limitation. In the case of an amino acid-imbalanced food source, this pathway has been shown to decrease food intake by activating a neuronal circuit. Taken together, the results discussed in this review demonstrate that amino acids by themselves can act as 'signal' molecules, with important roles in the control of gene expression and physiological functions

L’activation de la voie eIF2α-ATF4, une réponse adaptative au stress cellulaire

L’activation de la voie eIF2α-ATF4, une réponse adaptative au stress cellulair

Identification des mécanismes moléculaires impliqués dans la résistance des cellules à une carence en acides aminés

Cette année les assises sont en partenariat avec le Pôle de compétitivité Lyonbiopôle et le cluster Nutravita, des symposiums thématiques portant sur les interactions entre la recherche académique, l’innovation et l’industrie seront proposésLes cellules tumorales situées au coeur de tumeur sont soumises à une forte carence en nutriments et seules les cellules développant des mécanismes de résistance à ces carences vont pouvoir survivre. Les acides aminés (AA) sont particulièrement limitants du fait que certains AA ne peuvent pas être synthétisés de novo par la cellule. Dans un premier temps, face à un déficit en AA, la cellule va pouvoir s’adapter via la modulation de deux voies de signalisation: mTORC1 et GCN2/eIF2α/ATF4. Néanmoins cette adaptation ne peut être que transitoire, si le déficit perdure une sélection génétique des cellules acquérant des mécanismes de résistance peut s’opérer. Afin d’identifier ces mécanismes de résistance de cellules à un déficit prolongé en AA, nous avons développé un outil cellulaire par génétique fonctionnelle. Des fibroblastes embryonnaires de souris ont été soumis à une pression de sélection en les cultivant dans un milieu fortement carencé en AA pendant plusieurs mois ce qui a amené à la génération de clones capables de survire dans ce milieu. Contrairement aux cellules parentales, les clones ont la capacité de proliférer en milieu carencé en AA et de résister à la mort cellulaire induite par ce milieu. L’étude des voies de signalisation régulées par les AA a mis en évidence que malgré la phosphorylation d’eIF2α, le niveau d’expression d’ATF4 dans les clones est significativement plus faible que celui des cellules parentales. Cette sous-expression se traduit par un défaut d’expression des gènes cibles d’ATF4 dans les clones. L’étude de 2 lignées tumorales a mis en évidence une altération de la voie GCN2/eIF2α/ATF4 dans la lignée présentant la plus forte capacité de résistante à la carence en AA. Il n’existe pas de consensus dans la littérature quant au rôle de la voie GCN2/eIF2α/ATF4 en faveur de la survie ou la mort des cellules. Si la phosphorylation d’eIF2α ne semble pas délétère pour la survie, nos données suggèrent que l’expression d’ATF4 serait défavorable à la survie. D’autres expériences sont en cours afin de mieux caractériser le rôle de cette voie dans la survie des clone

Identification of molecular mechanisms involved in cancer cell resistance to amino acid deprivation

International audienc

Development and optimization of a new gene regulation system controlled by nutrition applicable for gene therapy

National audienc

The amino acid sensor GCN2 biases macronutrient selection during aging

International audiencePurpose Selection of a balanced diet has a determinant impact on human health. Individual food preferences involve socio-cultural as well as physiological factors and evolve during aging. In mammals, physiological mechanisms governing food choices appear to require the sensing of nutrient concentrations in diet. This is particularly the case for dietary amino acids that are sensed by the protein kinase GCN2. It has been reported that GCN2 is involved in the adaptive response to amino acid imbalanced diets at the level of food intake and lipid metabolism. Here, we hypothesized that GCN2 may play a role in macronutrient selection and its age-related changes. Methods Two groups of wild-type and GCN2 knock-out mice were subjected to a food self-selection protocol at ages 6, 12, 18 and 24 months. During each test, mice were allowed to create their own diets by selecting between three separate food sources, each containing either protein, fat or carbohydrates. Results Our results show that the absence of GCN2 had two main age-related effects. First, it exacerbated fat preference at the expense of carbohydrate consumption. Second, it prevented the increase in protein intake. Conclusion These findings indicate that, in omnivores, the GCN2 ancient pathway participates in the control of food preference