Biology subjects

Ardin, M.

Publications and source records attributed to Ardin, M..

6 recordsLinked to original sources

bioRxiv2023

Spatial transcriptomics reveal pitfalls and opportunities for the detection of rare high-plasticity breast cancer subtypes

Breast cancer is one of the most prominent types of cancers, in which therapeutic resistance is still a major clinical hurdle. Specific subtypes like Claudin-low (CL) and metaplastic breast cancers (MpBC) have been associated with high non-genetic plasticity, which can facilitate resistance. The overlaps and differences between these orthogonal subtypes, respectively identified by molecular and histopathological analyses, are however still insufficiently characterised. Adequate methods to identify high-plasticity tumours to better anticipate resistance are furthermore still lacking. Here we analysed 11 triple negative breast tumours, including 3 CL and 4 MpBC samples, via high-resolution spatial transcriptomics. We combined pathological annotations and deconvolution approaches to precisely identify tumour spots, on which we performed signature enrichment, differential expression and copy-number analyses. We used the TCGA and CCLE public databases for external validation of expression markers. By levying spatial transcriptomics to focus analyses only to tumour cells in MpBC samples, and therefore bypassing the negative impact of stromal contamination, we could identify specific markers that are not expressed in other subtypes nor stromal cells. Three markers (BMPER, POPDC3 and SH3RF3) could furthermore be validated in external expression databases encompassing bulk tumour material and stroma-free cell lines. We find that existing bulk expression signatures of high-plasticity breast cancers are relevant in mesenchymal transdifferentiated compartments but can be hindered by stromal cell prevalence in tumour samples, negatively impacting their clinical applicability. Spatial transcriptomics analyses can however help identify more specific expression markers, and could thus enhance diagnosis and clinical care of rare high-plasticity breast cancers.

cancer biology↗

bioRxiv2023

IL-33 drives polyfunctionality and antitumor activity of a unique ST2+ NK cell population

Despite increasing recognition of NK cell diversity, their functional heterogeneity and its relevance to cancer remain incompletely understood. Here, we show that IL-12 promotes the emergence of a distinct ST2/IL33R+ NK cell state poised for robust activation by IL-33. Human ST2 NK cells exhibit a unique transcriptional program, an intermediate differentiation state between CD56bright and CD56dim NK cells, and enhanced polyfunctionality combining proliferation, cytokine production, and cytotoxicity. ST2 NK cells were identified across human and murine tumor datasets. In murine breast cancer models, IL-33 and IL-12 cooperated to elicit potent antitumor responses dependent on IFN-{gamma} and ST2 NK cells. In cancer patients, IL-12 unleashed tumor-infiltrating ST2 NK cells' potential to produce IFN-g in response to IL-33, an IL33hi-NKhi score was associated with prolonged survival, and ST2 NK cells correlated with improved immunotherapy response. Collectively, these findings identify ST2 NK cells as a therapeutically actionable NK cell state promoting antitumor immunity.

cancer biology↗

bioRxiv2021

Disentangling heterogeneity of Malignant Pleural Mesothelioma through deep integrative omics analyses

Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell morphology, ploidy, adaptive immune response, and CpG island methylator phenotype. Previous genomic studies focused on describing only the tumor cell morphology factor, although we robustly find the three other sources in all publicly available cohorts. We prove how these sources of variation explain the biological functions performed by the cancer cells, and how genomic events shape MPM molecular profiles. We show how these new sources of variation help understand the heterogeneity of the clinical behavior of MPM and drug responses measured in cell lines. These findings unearth the interplay between MPM functional biology and its genomic history, and ultimately, inform classification, prognostication and treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/461908v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@b6c43corg.highwire.dtl.DTLVardef@10d45a9org.highwire.dtl.DTLVardef@58746eorg.highwire.dtl.DTLVardef@143f880_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Gene signature of circulating platelet-bound neutrophils is associated with poor prognosis in cancer patients

Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil-platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStream(R)X (ISX) imaging flow cytometer, we were not only allowed able to detect CD15+ CD14- CD36+ ITGA2B+ NPAs in both healthy donors (HDs) and cancer patients bloods, but we also showed that NPAs result from the binding of platelets preferentially to low-density neutrophils (LDNs) as opposed to normal-density neutrophils (NDNs). By re-analyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients derived NPAs possessed a distinct molecular signature compared with the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs-associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans-endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs-associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors. Novelty and ImpactPlatelets physically interact with peripheral blood neutrophils to form neutrophil-platelet aggregates (NPAs), known to promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. We showed that NPAs-associated neutrophils were a yet-unreported unique subset of circulating neutrophils associated with a worse patient prognosis in several cancer types. NPAs may hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors.

immunology↗

bioRxiv2018

Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide

Acrylamide, a probable human carcinogen, is ubiquitously present in the human environment, with sources including heated starchy foods, coffee and cigarette smoke. Humans are also exposed to acrylamide occupationally. Acrylamide is genotoxic, inducing gene mutations and chromosomal aberrations in various experimental settings. Covalent haemoglobin adducts were reported in acrylamide-exposed humans and DNA adducts in experimental systems. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic metabolite capable of inducing rodent tumors at various anatomical sites. In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and whole-exome sequencing analyses in an established exposure-clonal immortalization system based on mouse embryonic fibroblasts. Sequencing and computational analysis revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, followed by T:A>C:G and C:G>A:T mutations exhibiting specific trinucleotide contexts and significant transcription strand bias. Computational interrogation of human cancer genome sequencing data indicated that a combination of the glycidamide signature and an experimental benzo[a]pyrene signature are nearly equivalent to the COSMIC tobacco-smoking related signature 4 in lung adenocarcinomas and squamous cell carcinomas. We found a more variable relationship between the glycidamide- and benzo[a]pyrene-signatures and COSMIC signature 4 in liver cancer, indicating more complex exposures in the liver. Our study demonstrates that the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutation signature laboratory experimentation contributes to the elucidation of cancer causation.\n\nA 40-word summaryInnovative experimental approaches identify a novel mutational signature of glycidamide, a metabolite of the probable human carcinogen acrylamide. The results may elucidate the cancer risks associated with exposure to acrylamide, commonly found in tobacco smoke, thermally processed foods and beverages.

genomics↗

bioRxiv2017

Genome-Scale Mutational Signatures Of Aflatoxin In Cells, Mice And Human Tumors

Aflatoxin B1 (AFB1) is a mutagen and IARC Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here we present the first whole genome data on the mutational signatures of AFB1 exposure from a total of > 40,000 mutations in four experimental systems: two different human cell lines, and in liver tumors in wild-type mice and in mice that carried a hepatitis B surface antigen transgene - this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly-sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.

cancer biology↗