La régulation négative de la biogenèse des ribosomes : Une nouvelle voie de contrôle du cycle cellulaire par le suppresseur de tumeurs Arf ?

La prolifération cellulaire est intimement liée à la biogenèse des ribosomes dont dépendent les mécanismes fondamentaux de réplication, transcription, traduction. Toutefois, les arguments expérimentaux démontrant un lien direct entre la voie de biogenèse des ribosomes et le contrôle de la prolifération sont rares. Est-ce la prolifération anarchique des cellules qui induit l’activation de la synthèse des ribosomes ou, au contraire, est-ce qu’une synthèse accrue de ribosomes a pour conséquence une perte de contrôle de la prolifération ? Plusieurs suppresseurs de tumeurs sont connus aujourd’hui pour intervenir dans cette voie de biogenèse, le plus récemment décrit étant la protéine Arf qui contrôle négativement le cycle cellulaire par la voie classique Arf-Mdm2-p53. L’étude des fonctions suppresseurs de tumeurs de la protéine Arf, dans un contexte déficient en p53, a permis de montrer qu’elle exerce un contrôle négatif de la voie de biogenèse des ribosomes à deux niveaux. Au niveau transcriptionnel, en se liant directement au promoteur des ARNr, Arf réduit de 50 à 70 % la production du transcrit primaire ARNr 47S. Au niveau post-transcriptionnel, la maturation de cet ARNr 47S en ARNr matures 18S, 28S et 5,8S requiert l’endonucléase NPM/B23, régulée négativement par la protéine Arf. Cette nouvelle voie de contrôle de la prolifération est vraisemblablement mise en jeu lorsque la voie principale Arf-Mdm2-p53 est inopérante, mais rien n’empêche d’imaginer que les deux mécanismes coopèrent pour atteindre une meilleure efficacité du processus de suppression tumorale.The nucleolar Arf protein has initially been shown to regulate cell cycle through the so-called Arf-mdm2-p53 pathway. In addition to this well characterized pathway, convergent data published since 2000 indicate that Arf can inhibit cell proliferation in absence of p53, suggesting the existence of a p53-independent pathway. Several partners have recently been described that could participate in an alternative regulatory process. Recent results show that : (1) Arf binds the rDNA promoter to inhibit the transcription of the 47S rRNA precursor and (2) Arf interacts with the nucleophosmin/B23 protein to negatively regulate rRNA maturation, it is assumed that the tumour suppressor may downregulate the cell cycle progression through the control of ribosome biogenesis, thus resulting in completion of cell cycle arrest

Front Physiol

Glioblastoma is among the most common tumor of the central nervous system in adults. Overall survival has not significantly improved over the last decade, even with optimizing standard therapeutic care including extent of resection and radio- and chemotherapy. In this article, we review features of the brain vasculature found in healthy cerebral tissue and in glioblastoma. Brain vessels are of various sizes and composed of several vascular cell types. Non-vascular cells such as astrocytes or microglia also interact with the vasculature and play important roles. We also discuss engineered artificial blood vessels which may represent useful models for better understanding the tumor-vessel interaction. Finally, we summarize results from clinical trials with anti-angiogenic therapy alone or in combination, and discuss the value of these approaches for targeting glioblastoma

Deciphering the complex role of thrombospondin-1 in glioblastoma development

We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process

Adaptive coherence volume in full-field optical coherence tomography

International audienc

The Incubascope : a simple, compact and large field of view microscope for long-term imaging inside an incubator

Optical imaging has rapidly evolved in the last decades. Sophisticated microscopes allowing optical sectioning for 3D imaging or sub-diffraction resolution are available. Due to price and maintenance issues, these microscopes are often shared between users in facilities. Consequently, long term access is often prohibited and does not allow to monitor slowly evolving biological systems or to validate new models like organoids. Preliminary coarse long-term data that do not require acquisition of terabytes of high-resolution images are important as a first step. By contrast with expansive all-in-one commercialized stations, standard microscopes equipped with incubator stages offer a more cost-effective solution despite imperfect long run atmosphere and temperature control. Here, we present the Incubascope, a custom-made compact microscope that fits into a table-top incubator. It is cheap and simple to implement, user-friendly and yet provides high imaging performances. The system has a field of view of 5.5 × 8 mm 2 , a 3 µm resolution, a 10 frames/second acquisition rate, and is controlled with a Python-based graphical interface. We exemplify the capabilities of the Incubascope on biological applications such as the hatching of Artemia salina eggs, the growth of the slime mold Physarum polycephalum and of encapsulated spheroids of mammalian cells.Mécanotransduction des cellules souches adipeuses et applications pour l'ingénierie tissulaireElasticité et Dissipation des tissus en croissanceValidation translationnelle des greffes d'organoïdes neuraux pour le traitement des maladies de Parkinson et de Huntingto

Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence

International audienceSarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features. In mouse models of bone sarcoma, calpain-6-expressing cells have unique tumor-initiating and metastatic capacities. Calpain-6 levels are especially high in tumors that have been successfully propagated in mouse to establish patient-derived xenografts. We found that calpain-6 levels are increased by hypoxia in vitro and calpain-6 is detected within hypoxic areas in tumors. Furthermore, calpain-6 expression depends on the stem cell transcription network that involves Oct4, Nanog, and Sox2 and is activated by hypoxia. Calpain-6 knockdown blocks tumor development in mouse and induces depletion of the cancer stem cell population. Data from transcriptomic analyses reveal that calpain-6 expression in sarcomas inversely correlates with senescence markers. Calpain-6 knockdown suppresses hypoxia-dependent prevention of senescence entry and also promotion of autophagic flux. Together, our results demonstrate that calpain-6 identifies sarcoma cells with stem-like properties and is a mediator of hypoxia to prevent senescence, promote autophagy, and maintain the tumor-initiating cell population. These findings open what we believe is a novel therapeutic avenue for targeting sarcoma stem cells

Compressive stress triggers fibroblasts spreading over cancer cells to generate carcinoma in situ organization

Abstract At the early stage of tumor progression, fibroblasts are located at the outer edges of the tumor, forming an encasing layer around it. In this work, we have developed a 3D in vitro model where fibroblasts’ layout resembles the structure seen in carcinoma in situ. We use a microfluidic encapsulation technology to co-culture fibroblasts and cancer cells within hollow, permeable, and elastic alginate shells. We find that in the absence of spatial constraint, fibroblasts and cancer cells do not mix but segregate into distinct aggregates composed of individual cell types. However, upon confinement, fibroblasts enwrap cancer cell spheroid. Using a combination of biophysical methods and live imaging, we find that buildup of compressive stress is required to induce fibroblasts spreading over the aggregates of tumor cells. We propose that compressive stress generated by the tumor growth might be a mechanism that prompts fibroblasts to form a capsule around the tumor