Specialized Metabolites of the Lichen Vulpicida pinastri Act as Photoprotective Agents

International audienceThe extreme resiliency of lichens to UV radiations makes them an interesting model to find new photoprotective agents acting as UV-blockers and antioxidant. In this research, using a new in vitro method designed to overcome the shortage of material associated to many studies dealing with natural products, we show that the three major compounds isolated from the lichen Vulpicida pinastri, vulpinic acid, pinastric acid and usnic acid, were UV blocker agents. Antioxidant assays evidenced superoxide anion scavenging activity. Combination of the most promising compounds against UVB and UVB radiations, usnic acid, vulpinic acid and pinastric acid, increased the photoprotective activity. At the same time, they were found not cytotoxic on keratinocyte cell lines and photostable in the UVA and UVB ranges. Thus, lichens represent an attractive source to find good candidate ingredients as photoprotective agents. Additionally, the uncommon scalemic usnic acid mixture in this Vulpicida species was proven through electronic circular dichroism calculation

Insuffisance ovarienne prématurée sévère : pensez aux hommes !

National audienc

Infertilité masculine et féminine liés à SYCE1 : cas d’une délétion récurrente en 10q26.3

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Clear cell renal cell carcinoma: a comparative study of histological and chromosomal characteristics between primary tumors and their corresponding metastases

International audienceClear cell renal cell carcinoma (ccRCC) has a poor prognosis with a 50% risk of metastases. Little is known about the phenotypic and molecular profiles of metastases regarding their corresponding primary tumors. This study aimed to screen phenotypic and genotypic differences between metastases and their corresponding primary tumors. We selected four cases with available frozen material. The histological, immunohistochemical (VEGFA, CD31, SMA, Ki67, p53, PAR-3), FISH (VHL gene), next-generation sequencing (VHL and c-MET genes), multiplex ligation-dependent probe amplification, and array-(comparative genomic hybridization) CGH analyses were realized. Metastases were nodal, hepatic (synchronous), adrenal, and pulmonary (metachronous). High-grade tumor cells were significantly more frequent in metastases (p = 0.019). Metastases and high-grade zones of primary tumors shared similar characteristics compared to low-grade zones: a lower microscopic vascular density (43.5 vs 382.5 vessels/mm(2); p = 0.0027), a higher expression of VEGF (73 vs 10%, p = 0.045), Ki67 (37.6 vs 8.3%; p = 0.011), and p53 (54 vs 10.6%; p = 0.081), and a cytoplasmic and membranous PAR-3 staining. Metastases exhibited more chromosomal imbalances than primary tumors in total (18.75 ± 6.8; p = 0.044) with more genomic gains (13.5 ± 7; p = 0.013). The loss of chromosome 9 and gain of Xq were found in both primary tumors and metastases but gains of loci or chromosomes 2p, 3q, 5, 8q, 12, and 20 were only found in metastases. The VHL gene status was similar in each tumor couple. Although metastases and primary tumors share common histological features, this study highlights chromosomal differences specific to metastases which could be involved in ccRCC metastatic evolution

Multiple metastatic clones assessed by an integrative multiomics strategy in clear cell renal carcinoma: a case study

International audienceThe dynamics of metastatic evolution in clear cell renal cell carcinoma (ccRCC) are complex. We report a case study where tumour heterogeneity resulting from clonal evolution is a frequent feature and could play a role in metastatic dissemination.We used an integrative multiomics strategy combining genomic and transcriptomic data to classify fourteen specimens from spatially different areas of a kidney tumour and three non-primary sites including a vein thrombus and two adrenal metastases.All sites were heterogeneous and polyclonal, each tumour site containing two different aggressive subclonal populations, with differentially expressed genes implicated in distinct biological functions. These are rare primary metastatic samples prior to any medical treatment, where we showed a multiple metastatic seeding of two subclonal populations.Multiple interdependent lineages could be the source of metastatic heterogeneity in ccRCC. By sampling metastases, patients with resistance to therapies could benefit a combination of targeted therapies based on more than one aggressive clone

Étude du profil histologique et moléculaire des carcinomes rénaux à cellules claires et leurs métastases

National audienceLe carcinome rénal à cellules claires (CCCR) est la forme histologique la plus fréquente des cancers du rein. Au cours de l’évolution, si le patient progresse sous traitement, les métastases sont rarement biopsiées. Leur profil phénotypique et moléculaire par rapport à la tumeur d’origine est mal connu. Trois patients ayant un CCCR opéré par néphrectomie totale ou partielle, avec métastase synchrone ou métachrone (hépatique, ganglionnaire, et pulmonaire) ont été inclus rétrospectivement. Les prélèvements tumoraux ont été analysés sur le plan histologique, immuno-histochimique (VEGF-A, CD31-AML, Ki67, p53 et PAR-3), cytogénétique (ACPA, FISH), et moléculaire (NGS : statut du gène VHL : délétion, mutation et/ou hyperméthylation du promoteur). L’aspect histologique et immuno-histochimique des métastases était superposable à la composante de plus haut grade de la tumeur primitive, toutes les tumeurs étant de grade 4 de Fuhrman. Les analyses par FISH et NGS ont mis en évidence une délétion hétérozygote du gène VHL et la présence de la même mutation dans chacun des couples tumeur primitive/métastase, sans hyperméthylation du promoteur. L’ACPA a comparé l’ADN des métastases à celui des tumeurs primitives et a montré des profils chromosomiques distincts. Par rapport à leur tumeur primitive, un gain en 3q22 (environ 1 Mb) a été retrouvé dans les métastases de tous les patients. Cette région contient des gènes (PPP2R3A, STAG1, MSL2, NCK1, TMEM22) qui pourraient être impliqués dans la prolifération des cellules tumorales et/ou dissémination métastatique. En particulier, la surexpression de la protéine TMEM22 a été décrite comme favorisant la croissance des cellules des carcinomes rénaux à cellules claires. Ce travail confirme que le profil chromosomique des métastases des CRCC est distinct de celui des tumeurs primitives. Des études complémentaires sont en cours pour préciser l’implication de gènes de la région 3q22 dans le potentiel métastatique des CRC

Prognostic value of somatic focal amplifications on chromosome 30 in canine oral melanoma

International audienceCanine oral melanoma is the first malignancy of the oral cavity in dogs and is characterized by a local invasiveness and a high metastatic propensity. A better knowledge of genetic alterations is expected to improve management of this tumour. Copy number alterations are known characteristics of mucosal melanomas both in dogs and humans. The goal of this study was to explore the prognostic value of somatic focal amplifications on chromosomes (Canis Familiaris [CFA]) 10 and 30 in canine oral melanoma. The cohort included 73 dogs with oral melanoma confirmed by histology, removed surgically without adjuvant therapy and with a minimal follow‐up of 6 months. Epidemiological, clinical and histological data were collected and quantitative‐PCR were performed on formalin‐fixed paraffin‐embedded (FFPE) samples to identify specific focal amplifications. The 73 dogs included in the study had a median survival time of 220 days. Focal amplifications on CFA 10 and 30 were recurrent (49.3% and 50.7% of cases, respectively) and CFA 30 amplification was significantly associated with the amelanotic phenotype (P = .046) and high mitotic index (MI; P = .0039). CFA 30 amplification was also linked to poor prognosis (P = .0005). Other negative prognostic factors included gingiva location (P = .003), lymphadenomegaly (P = .026), tumour ulceration at diagnosis (P = .003), MI superior to 6 mitoses over 10 fields (P = .001) and amelanotic tumour (P = .029). In multivariate analyses using Cox proportional hazards regression, CFA 30 amplification (Hazard ratio [HR] = 2.08; P = .011), tumour location (HR = 2.20; P = .005) and histological pigmentation (HR = 1.87; P = .036) were significantly associated with shorter survival time. Focal amplification of CFA 30 is linked to an aggressive subset and constitutes a new prognostic factor

Canine Oral Melanoma Genomic and Transcriptomic Study Defines Two Molecular Subgroups with Different Therapeutical Targets

Simple Summary In humans, mucosal melanoma (MM) is a rare and aggressive cancer. The canine model is frequently and spontaneously affected by MM, thus facilitating the collection of samples and the study of its genetic bases. Thanks to an integrative genomic and transcriptomic analysis of 32 canine MM samples, we identified two molecular subgroups of MM with a different microenvironment and structural variant (SV) content. We demonstrated that SVs are associated with recurrently amplified regions, and identified new candidate oncogenes (TRPM7, GABPB1, and SPPL2A) for MM. Our findings suggest the existence of two MM molecular subgroups that could benefit from dedicated therapies, such as immune checkpoint inhibitors or targeted therapies, for both human and veterinary medicine. Mucosal melanoma (MM) is a rare, aggressive clinical cancer. Despite recent advances in genetics and treatment, the prognosis of MM remains poor. Canine MM offers a relevant spontaneous and immunocompetent model to decipher the genetic bases and explore treatments for MM. We performed an integrative genomic and transcriptomic analysis of 32 canine MM samples, which identified two molecular subgroups with a different microenvironment and structural variant (SV) content. The overexpression of genes related to the microenvironment and T-cell response was associated with tumors harboring a lower content of SVs, whereas the overexpression of pigmentation-related pathways and oncogenes, such as TERT, was associated with a high SV burden. Using whole-genome sequencing, we showed that focal amplifications characterized complex chromosomal rearrangements targeting oncogenes, such as MDM2 or CDK4, and a recurrently amplified region on canine chromosome 30. We also demonstrated that the genes TRPM7, GABPB1, and SPPL2A, located in this CFA30 region, play a role in cell proliferation, and thus, may be considered as new candidate oncogenes for human MM. Our findings suggest the existence of two MM molecular subgroups that may benefit from dedicated therapies, such as immune checkpoint inhibitors or targeted therapies, for both human and veterinary medicine

Discovery of Human-Similar Gene Fusions in Canine Cancers

International audienceCanine cancers represent a tremendous natural resource due to their incidence and striking similarities to human cancers, sharing similar clinical and pathologic features as well as oncogenic events, including identical somatic mutations. Considering the importance of gene fusions as driver alterations, we explored their relevance in canine cancers. We focused on three distinct human-comparable canine cancers representing different tissues and embryonic origins. Through RNA-Seq, we discovered similar gene fusions as those found in their human counterparts: IGK-CCND3 in B-cell lymphoma, MPB-BRAF in glioma, and COL3A1-PDGFB in dermatofibrosarcoma protuberans-like. We showed not only similar partner genes but also identical breakpoints leading to oncogene overexpression. This study demonstrates similar gene fusion partners and mechanisms in human-dog corresponding tumors and allows for selection of targeted therapies in preclinical and clinical trials with pet dogs prior to human trials, within the framework of personalized medicine