Simultaneous growth of two cancer cell lines evidences variability in growth rates

Cancer cells co-cultured in vitro reveal unexpected differential growth rates that classical exponential growth models cannot account for. Two non-interacting cell lines were grown in the same culture, and counts of each species were recorded at periodic times. The relative growth of population ratios was found to depend on the initial proportion, in contradiction with the traditional exponential growth model. The proposed explanation is the variability of growth rates for clones inside the same cell line. This leads to a log-quadratic growth model that provides both a theoretical explanation to the phenomenon that was observed, and a better fit to our growth data

nwCompare and AutoCompare Softwares for Proteomics and Transcriptomics Data Mining – Application to the Exploration of Gene Expression Profiles of Aggressive Lymphomas

chapitre 22International audienc

ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks

Summary: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Purpose Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. Results We identified five functional variants inTHSD4of which two heterozygous variants lead to a premature termination codon.THSD4encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. TheTHSD4variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils.Thsd4(+/-)mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying aTHSD4variant and fromThsd4(+/-)mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. Conclusion These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies

Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors

Etude des populations immunitaires régulatrices et inflammatoires dans les cancers colorectaux

Anti-tumoral immunity has been argued for ages. Nowadays, a lot of studies demonstrate specific anti-tumoral response. Tumor-infiltrating T cells (TILs) are associated with the inhibition of tumor development and with the clinical outcome. However the presence of a tumor despite the immune system highlights escape mechanisms. First, I contributed to the characterization of the prognostic value of lymphocyte markers. The density of T lymphocyte and memory T lymphocyte, and their localization in the center and the invasive margin of the tumor, were associated with improved clinical outcome. This immune classification was more significant than the usual parameter to identify patients who relapse. We also showed the impairment of the immune response coordination when lymph nodes or distant organs were invaded. I analyzed the cytotoxic CD8 T cells markers in relation with helper T subpopulations. We found functional clusters that are associated with clinical outcome. Patients with high expression of the Th1/cytotoxic cluster had prolonged disease-free survival. In contrast, patients with high expression of the Th17 cluster had poor prognosis. The combined analysis of cytotoxic and Th17 cluster gave a better discrimination for relapse. microRNA are involved in a lot of biological process including the immune system or cancer. I studied their profile of expression in normal and tumoral tissues. Their profiles were different with higher and lower level of some microRNAs. I also observed the association of some microRNAs with a particular clinical outcome and with immune system marker. All this work shows the importance of the immune system in the prediction of clinical outcome. The immune evaluation within the standard procedure would better determine the best therapy.L'existence d'une immunité anti-tumorale a longtemps été controversée. Aujourd'hui, de nombreuses études ont montré des réponses anti-tumorales spécifiques. Les lymphocytes infiltrant la tumeur (TIL) jouent un rôle dans l'inhibition de la croissance des tumeurs et sont associés à un meilleur pronostic. Cependant, la présence d'une tumeur malgré le système immunitaire met en évidence des mécanismes d'échappement. J'ai tout d'abord participé à la caractérisation de la valeur pronostic de marqueurs lymphocytaires. La densité de l'infiltrat lymphocytaire T, en particulier les lymphocytes T mémoires, et leurs localisations au niveau du centre et du front de progression de la tumeur sont associées au devenir clinique des patients. Ces paramètres permettent une classification des patients à risque élevé de récidive bien plus significative que les paramètres anatomopathologiques. En étudiant plus précisément ces paramètres, nous avons montré l'altération progressive des réponses immunitaires anti-tumorales lors de l'envahissement des ganglions ou d'organes à distance. Je me suis donc intéressée aux marques de cytotoxicité en relation avec les différentes sous-populations T helper. Nous avons à nouveau trouvé des clusters fonctionnels mais seuls les réponses Th1, cytotoxique et Th17 sont associées au pronostic des patients. Les patients avec une forte réponse Th1 ou cytotoxique sont de bon pronostic tandis que ceux avec une forte réponse Th17 sont de mauvais pronostic. La combinaison de ces paramètres est plus discriminante pour déterminer les patients à risque de récidive. Les microARNs interviennent dans de nombreux processus biologiques physiologiques (dont le système immunitaire) et physiopathologiques (dont le cancer). J'ai étudié leurs profils d'expression dans des colons sains et tumoraux. Ces profils sont différents, avec des sur-expressions et sous-expressions de certains microARNs. J'ai également observé l'association de certains microARNs au devenir clinique de patients mais aussi à des marqueurs du système immunitaire. L'ensemble des travaux réalisés montre l'importance de la réaction immunitaire adaptative pour l'établissement du pronostic des patients atteints de cancers colorectaux. Son évaluation en routine permettrait de mieux orienter les patients vers une stratégie thérapeutique adaptée

Etude des populations immunitaires régulatrices et inflammatoires dans les cancers colorectaux

L existence d une immunité anti-tumorale a longtemps été controversée. Aujourd hui, de nombreuses études ont montré des réponses anti-tumorales spécifiques. Les lymphocytes infiltrant la tumeur (TIL) jouent un rôle dans l inhibition de la croissance des tumeurs et sont associés à un meilleur pronostic. Cependant, la présence d une tumeur malgré le système immunitaire met en évidence des mécanismes d échappement. J ai tout d abord participé à la caractérisation de la valeur pronostic de marqueurs lymphocytaires. La densité de l infiltrat lymphocytaire T, en particulier les lymphocytes T mémoires, et leurs localisations au niveau du centre et du front de progression de la tumeur sont associées au devenir clinique des patients. Ces paramètres permettent une classification des patients à risque élevé de récidive bien plus significative que les paramètres anatomopathologiques. En étudiant plus précisément ces paramètres, nous avons montré l altération progressive des réponses immunitaires anti-tumorales lors de l envahissement des ganglions ou d organes à distance. Je me suis donc intéressée aux marques de cytotoxicité en relation avec les différentes sous-populations T helper. Nous avons à nouveau trouvé des clusters fonctionnels mais seuls les réponses Th1, cytotoxique et Th17 sont associées au pronostic des patients. Les patients avec une forte réponse Th1 ou cytotoxique sont de bon pronostic tandis que ceux avec une forte réponse Th17 sont de mauvais pronostic. La combinaison de ces paramètres est plus discriminante pour déterminer les patients à risque de récidive. Les microARNs interviennent dans de nombreux processus biologiques physiologiques (dont le système immunitaire) et physiopathologiques (dont le cancer). J ai étudié leurs profils d expression dans des colons sains et tumoraux. Ces profils sont différents, avec des sur-expressions et sous-expressions de certains microARNs. J ai également observé l association de certains microARNs au devenir clinique de patients mais aussi à des marqueurs du système immunitaire. L ensemble des travaux réalisés montre l importance de la réaction immunitaire adaptative pour l établissement du pronostic des patients atteints de cancers colorectaux. Son évaluation en routine permettrait de mieux orienter les patients vers une stratégie thérapeutique adaptée.Anti-tumoral immunity has been argued for ages. Nowadays, a lot of studies demonstrate specific anti-tumoral response. Tumor-infiltrating T cells (TILs) are associated with the inhibition of tumor development and with the clinical outcome. However the presence of a tumor despite the immune system highlights escape mechanisms. First, I contributed to the characterization of the prognostic value of lymphocyte markers. The density of T lymphocyte and memory T lymphocyte, and their localization in the center and the invasive margin of the tumor, were associated with improved clinical outcome. This immune classification was more significant than the usual parameter to identify patients who relapse. We also showed the impairment of the immune response coordination when lymph nodes or distant organs were invaded. I analyzed the cytotoxic CD8 T cells markers in relation with helper T subpopulations. We found functional clusters that are associated with clinical outcome. Patients with high expression of the Th1/cytotoxic cluster had prolonged disease-free survival. In contrast, patients with high expression of the Th17 cluster had poor prognosis. The combined analysis of cytotoxic and Th17 cluster gave a better discrimination for relapse. microRNA are involved in a lot of biological process including the immune system or cancer. I studied their profile of expression in normal and tumoral tissues. Their profiles were different with higher and lower level of some microRNAs. I also observed the association of some microRNAs with a particular clinical outcome and with immune system marker. All this work shows the importance of the immune system in the prediction of clinical outcome. The immune evaluation within the standard procedure would better determine the best therapyPARIS-BIUP (751062107) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Single-Cell Signature Explorer for comprehensive visualization of single cell signatures across scRNA-seq datasets

International audienc

Paleocene high-latitude leaf flora of Antarctica Part 1: Entire-margined angiosperms

Paleocene leaf floras are rare in high latitudes of the Southern Hemisphere, where studies have shown higher taxonomic diversity compared to Northern Hemisphere equivalents. The floras provide valuable insights into biodiversity and forest communities during the Paleocene. The Antarctic Peninsula hosts a wealth of Paleocene–Eocene floras which have been used to interpret climates before, during and after one of the most abrupt and transient warming events known from the geological record. The best-preserved and most diverse Paleocene macrofossils from this region come from the Cross Valley Formation, Seymour Island Group, which have previously provided evidence for warm temperate climates prior to the PETM. Here we present the taxonomy of leaf impressions from the Paleocene Cross Valley Flora for one species and ten new leaf morphotypes of entire-margined angiosperms. The new morphotypes provide evidence of an increased angiosperm diversity within cool-temperate Gondwanan forest inhabiting the east side of the Antarctic Peninsula, which contrasts with a lower floral diversity on the west side of the Peninsula during the late Paleocene